Benzylcycloalkyl amines as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of CCR3 of formula (I):  
                 
 
     or pharmaceutically acceptable salt forms thereof, useful for the prevention of inflammatory diseases such as asthma and other allergic diseases.

FIELD OF THE INVENTION

[0001] This invention relates generally to modulators of chemokinereceptor activity, pharmaceutical compositions containing the same, andmethods of using the same as agents for treatment and prevention ofinflammatory diseases such as allergic diseases and asthma, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

[0002] Chemokines are chemotactic cytokines, of molecular weight 6-15kDa, that are released by a wide variety of cells to attract andactivate, among other cell types, macrophages, T and B lymphocytes,eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. JMed., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). Thereare two major classes of chemokines, CXC and CC, depending on whetherthe first two cysteines in the amino acid sequence are separated by asingle amino acid (CXC) or are adjacent (CC). The CXC chemokines, suchas interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and-3) are chemotactic for, among other cell types, macrophages, Tlymphocytes, eosinophils, dendritic cells, and basophils. There alsoexist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines),and fractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

[0003] The chemokines bind to specific cell-surface receptors belongingto the family of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal through theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425(1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91,2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or“CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898(1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J.Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”)[I-309, TARC, MIP-1β] (Napolitano et al., J. Immunol., 157, 2759-2763(1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); andCCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNAand Cell Biol., 16, 1249-1256 (1997)).

[0004] In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed by Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

[0005] Chemokine receptors have been implicated as being importantmediators of inflammatory, infectious, and immunoregulatory disordersand diseases, including asthma and allergic diseases, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis.For example, the chemokine receptor CCR-3 plays a pivotal role inattracting eosinophils to sites of allergic inflammation and insubsequently activating these cells. The chemokine ligands for CCR-3induce a rapid increase in intracellular calcium concentration,increased expression of cellular adhesion molecules, cellulardegranulation, and the promotion of eosinophil migration. Accordingly,agents which modulate chemokine receptors would be useful in suchdisorders and diseases. In addition, agents which modulate chemokinereceptors would also be useful in infectious diseases such as byblocking infection of CCR3 expressing cells by HIV or in preventing themanipulation of immune cellular responses by viruses such ascytomegaloviruses.

[0006] A substantial body of art has accumulated over the past severaldecades with respect to substituted piperidines and pyrrolidines. Thesecompounds have implicated in the treatment of a variety of disorders.

[0007] WO 98/25604 describes spiro-substituted azacycles which areuseful as modulators of chemokine receptors:

[0008] wherein R₁ is C₁₋₆ alkyl, optionally substituted with functionalgroups such as —NR⁶CONHR⁷, wherein R⁶ and R⁷ may be phenyl furthersubstituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spirocompounds are not considered part of the present invention.

[0009] WO 95/13069 is directed to certain piperidine, pyrrolidine, andhexahydro-1H-azepine compounds of general formula:

[0010] wherein A may be substituted alkyl or Z-substituted alkyl, withZ═NR_(6a) or O. Compounds of this type are claimed to promote therelease of growth hormone in humans and animals.

[0011] WO 93/06108 discloses pyrrolobenzoxazine derivatives as5-hydroxytryptamine (5-HT) agonists and antagonists:

[0012] wherein A is lower alkylene and R⁴ may be phenyl optionallysubstituted with halogen.

[0013] U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY)antagonists comprising 1,4-dihydropyridines with a piperidinyl ortetrahydropyridinyl-containing moiety attached to the 3-position of the4-phenyl ring:

[0014] wherein B may be NH, NR¹, O, or a bond, and R⁷ may be substitutedphenyl, benzyl, phenethyl and the like.

[0015] Patent publication EP 0 903 349 A2 discloses CCR-3 receptorantagonists comprising cyclic amines of the following structure:

[0016] wherein T and U may be both nitrogen or one of T and U isnitrogen and the other is carbon and E may be —NR⁶CONR⁵— and others.

[0017] These reference compounds are readily distinguished structurallyby either the nature of the urea functionality, the attachment chain, orthe possible substitution of the present invention. The prior art doesnot disclose nor suggest the unique combination of structural fragmentswhich embody these novel piperidines and pyrrolidines as having activitytoward the chemokine receptors.

SUMMARY OF THE INVENTION

[0018] Accordingly, one object of the present invention is to providenovel agonists or antagonists of CCR-3, or pharmaceutically acceptablesalts or prodrugs thereof.

[0019] It is another object of the present invention to providepharmaceutical compositions comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

[0020] It is another object of the present invention to provide a methodfor treating inflammatory disorders comprising administering to a hostin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

[0021] These and other objects, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of formula (I):

[0022] or stereoisomers or pharmaceutically acceptable salts thereof,wherein A, G, R¹, R⁴, R⁴′, R⁵, R¹⁷, n and u are defined below, areeffective modulators of chemokine activity.

DETAILED DESCRIPTION OF THE EMBODIMENTS [1] Thus, in a first embodiment,the present invention provides novel compounds of formula (I):

[0023]

[0024] or stereoisomers or pharmaceutically acceptable salts thereof,wherein:

[0025] A is selected from

[0026] G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³,—SO₂R³, —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,C(═C(CN)₂)NR²R³,

[0027] W, at each occurrence, is independently selected from C or N,provided at least two of W are C;

[0028] X is selected from O, S, and NR¹⁹;

[0029] X¹ and X² are independently selected from C and N;

[0030] Z¹ is selected from C and N;

[0031] Z² is selected from NR^(1a), O, S and C;

[0032] R¹ and R² are independently selected from H, C₁₋₈ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(a);

[0033] R^(1a) is independently selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(a);

[0034] R^(a), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH,(CH₂)_(r)OR^(c), (CH₂)_(r)SH, (CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b),(CH₂)_(r)C(O)NR^(b)R^(b), (CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b),(CH₂)_(r)OC(O)R^(c), (CH₂)_(r)CH(═NR^(b))NR^(b)R^(b),(CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b), (CH₂)_(r)S(O) _(p)R^(c),(CH₂)_(r)S(O)₂NR^(b)R^(b), (CH₂)_(r)NR^(b)S(O)₂R^(c), and(CH₂)_(r)phenyl;

[0035] R^(b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

[0036] R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

[0037] alternatively, R² and R³ join to form a 5, 6, or 7-membered ringsubstituted with 0-3 R^(a);

[0038] R³ is selected from a (CR³′R³″)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R¹⁵ and a (CR³′R³″)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R¹⁵;

[0039] R³′ and R³″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

[0040] R⁴ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(a);

[0041] alternatively, R⁴ joins with R⁸ or R¹¹ to form a pyrrolidine orpiperidine ring system substituted with 0-3 R^(4d);

[0042] R⁴′ is absent, taken with the nitrogen to which it is attached toform an N-oxide, or selected from C₋₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4a), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c);

[0043] R^(4a) and R^(4a)′, at each occurrence, are selected from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

[0044] R^(4b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;

[0045] R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl;

[0046] R^(4d), is selected from H, C₁₋₆ alkyl, (CHR′)_(q)OH,(CHR′)_(q)OR^(7a), (CHR′)_(q)OC(O)R^(7b), (CHR′)_(q)OC(O)NHR^(7a);

[0047] R⁵ is selected from a (CR⁵′R⁵″)_(t)—C₃₋₁₀ _(³¹⁰) carbocyclicresidue substituted with 0-5 R¹⁶¹⁶ and a (CR⁵′R⁵″)t-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R¹⁶¹⁶;

[0048] R⁵′⁵ and R⁵″⁵, at each occurrence, are selected from H, C₁₋₆_(¹⁶) alkyl, (CH₂₂)_(r)C₃₋₆ _(³⁶) cycloalkyl, and phenyl;

[0049] R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CHR′)_(q)OH, (CHR′)_(q)SH, (CHR′)_(q)OR^(7d), (CHR′)_(q)SR^(7d),(CHR′)_(q)NR^(7a)R^(7a)′, (CHR′)_(q)C(O)OH, (CHR′)_(r)C(O)R^(7b),(CHR′)_(q)C(O)NR^(7a)R^(7a)″, (CHR′)_(q)NR^(7a)C(O)R^(7a),(CHR′)_(q)NR^(7a)C(O)H, (CHR′)_(q)C(O)OR^(7a), (CHR′)_(q)OC(O)R^(7b),(CHR′)_(q)S(O)_(p)R^(7b), (CHR′)_(q)S(O)₂NR^(7a)R^(7a)′,(CHR′)_(q)NR^(7a)S(O)₂R^(7b), (CHR′)_(q)NHC(O)NR^(7a)′R^(7a),(CHR′)_(q)NHC(O)OR^(7a), (CHR′)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a(CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c), and a(CHR′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7c);

[0050] R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(7e);

[0051] R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(7e), and a (CH₂)_(r)-⁵-⁶ membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(7e);

[0052] R^(7c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,-I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-3 R^(7e);

[0053] R^(7d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(7e), and a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(7c);

[0054] R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(q)OH, OH, (CH₂)_(q)SH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(q)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

[0055] R^(7f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0056] R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(8a);

[0057] R^(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

[0058] alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, or═NR^(8b);

[0059] R^(8b) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN,and (CH₂)_(r)-phenyl;

[0060] R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d),(CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)C(O)R^(11b),(CH₂)_(q)NR^(11a)C(O)NR^(11a)′R^(11a), (CH₂)_(r)C(O)OR^(11a),(CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with:0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);

[0061] R^(11a) and R^(11a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(11e);

[0062] R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(11e), and a (CH₂)_(r)-5-⁶ membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e);

[0063] R^(11c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e);

[0064] R^(11d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(11c);

[0065] R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;

[0066] R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0067] R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

[0068] R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenylsubstituted with R^(15e);

[0069] R^(15a) and R^(15a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(15e);

[0070] R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(15e);

[0071] R^(15d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(15e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(15e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(15e);

[0072] R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC¹⁻⁵ alkyl,(CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl;

[0073] R^(15f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

[0074] R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)NHC(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

[0075] R^(16a) and R^(16a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(16e);

[0076] R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substitutedwith 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(16e);

[0077] R^(16d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(16e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e), and a(CH₂)_(r)-5-⁶ membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(16e);

[0078] R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl;

[0079] R^(16f), at each occurrence, is selected from H, C₁₋₅ alkyl, andC₃₋₆ cycloalkyl, and phenyl;

[0080] R¹⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(17d), (CH₂)_(q)SR^(17d),(CH₂)_(q)NR^(17a)R^(17a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(17b),(CH₂)_(r)C(O)NR^(17a)R^(17a)′, (CH₂)_(q)NR^(17a)C(O)R^(17b),(CH₂)_(q)NR^(17a)C(O)H, (CH₂)_(r)C(O)OR^(17a), (CH₂)_(q)OC(O)R^(17b),(CH₂)_(q)S(O)_(p)R^(17b), (CH₂)_(q)S(O)₂NR^(17a)R^(17a)′,(CH₂)_(q)NR^(17a)S(O)₂R^(17b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(17c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(17c);

[0081] R^(17a) and R^(17a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(17e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(17e);

[0082] R^(17b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(17e), and a (CH₂)_(r)-5-⁶ membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(17e);

[0083] R^(17c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(17f)R^(17f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(17b), (CH₂)_(r)C(O)NR^(17f)R^(17f),(CH₂)_(r)NR^(17f)C(O)R^(17a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(17b), (CH₂)_(r)C(═NR^(17f))NR^(17f)R^(17f),(CH₂)_(r)S(O)_(p)R^(17b), (CH₂)_(r)NHC(═NR^(17f))NR^(17f)R^(17f),(CH₂)_(r)S(O)₂NR^(17f)R^(17f), (CH₂)_(r)NR^(17f)S(O)₂R^(17b), and(CH₂)_(r)phenyl substituted with 0-3 R^(17e);

[0084] R^(17d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(17e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(17c);

[0085] R^(17e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(17f)R^(17f), and (CH₂)_(r)phenyl;

[0086] R^(17f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0087] R¹⁸; is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CHR′)_(q)OH, (CHR′)_(q)SH, (CHR′)_(q)OR^(18d), (CHR′)_(q)SR^(18d),(CHR′)_(q)NR^(18a)R^(18a)′, (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(18b),(CHR′)_(r)C(O)NR^(18a)R^(18a)′, (CHR′)_(q)NR^(18a)C(O)R^(18a),(CHR′)_(q)NR^(18a)C(O)H, (CHR′)_(r)C(O)OR^(18a), (CHR′)_(q)OC(O)R^(18b),(CHR′)_(q)S(O)_(p)R^(18b), (CHR′)_(q)S(O)₂NR^(18a)R^(18a)′,(CHR′)_(q)NR^(18a)S(O)₂R^(18b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(18c), and a (CHR′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with ₀-₂ R^(18c);

[0088] R^(18a) and R^(18a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(18e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(18e);

[0089] R^(18b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(18e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(18e);

[0090] R^(18c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(18f)R^(18f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(18b), (CH₂)_(r)C(O)NR^(18f)R^(18f),(CH₂)_(r)NR^(18f)C(O)R^(18a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(18b), (CH₂)_(r)C(═NR^(18f))NR^(18f)R^(18f),(CH₂)_(r)S(O)_(p)R^(18b), (CH₂)_(r)NHC(═NR^(18f))NR^(18f)R^(18f),(CH₂)_(r)S(O)₂NR^(18f)R^(18f), (CH₂)_(r)NR^(18f)S(O)₂R^(18b), and(CH₂)_(r)phenyl substituted with 0-3 R^(18e);

[0091] R^(18d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(18e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(18c);

[0092] R^(18e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(18f)R^(18f), and (CH₂)_(r)phenyl;

[0093] R^(18f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0094] R¹⁹ is selected from C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,—C(O)R^(19b), —C(O)NR^(19a)R^(19a), —C(O)OR^(19a), and —SO₂R^(19a), a(CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁶, and a(CHR′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R¹⁶;

[0095] R^(19a) is selected from C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,C₃₋₆ cycloalkyl, a (CR⁵′⁵R⁵″)_(t)—C₃₋₁₀ _(³¹⁰) carbocyclic residuesubstituted with 0-5 R¹⁵¹⁶ and a (CR⁵′⁵R⁵″⁵) _(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R¹⁶¹⁶;

[0096] R^(19b) is selected from H, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, C₃₋₆ cycloalkyl, a (CR⁵′R⁵″)_(t)—C₃₋₁₀ _(³¹⁰) carbocyclicresidue substituted with 0-5 R¹⁵¹⁶ and a (CR⁵′R⁵″)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R¹⁶¹⁶;

[0097] m, at each occurrence, is selected from 1, 2, 3, 4, and 5;

[0098] n, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;

[0099] o, at each occurrence, is selected from 1 and 2;

[0100] p, at each occurrence, is selected from 1 and 2;

[0101] r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;

[0102] q, at each occurrence, is selected from 1, 2, 3, 4, and 5;

[0103] s, at each occurrence, is selected from 0, 1, and 2;

[0104] t, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;

[0105] u, at each occurrence, is independently selected from 0, 1, and2;

[0106] v, at each occurrence, is selected from 0 and 1; and

[0107] w, at each occurrence, is selected from 0, 1, 2, and 3.

[0108] [2] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0109] R⁴′ is absent or, taken with the nitrogen to which it is attachedto form an N-oxide;

[0110] R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CHR′)_(q)OH, (CHR′)_(q)OR⁷d, (CHR′)_(q)NR^(7a)R^(7a)′,(CHR′)_(q)C(O)R^(7b), (CHR′)_(q)C(O)NR^(7a)R^(7a)′,(CHR′)_(q)NR^(7a)C(O)R^(7b), (CHR′)_(q)NR^(7a)C(O)H,(CHR′)_(q)S(O)₂NR^(7a)R^(7a)′, (CHR′)_(q)NR^(7a)S(O)₂R^(7b),(CHR′)_(q)NHC(O)NHR^(7a), (CHR′)_(q)NHC(O)OR^(7a),(CHR′)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(7c), and a (CHR′)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7c);

[0111] alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, or═NR^(8b);

[0112] R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a)′,(CH₂)_(q)NR^(11a)C(O)R^(11b), (CH₂)_(q)NR^(11a)C(O)NHR^(11a),(CH₂)_(q)NHC(O)NHR^(11a), (CH₂)_(q)NHC(O)OR^(11a),(CH₂)_(q)OC(O)NHR^(11a), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(11c), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(11c).

[0113] [3] In another embodiment, the present invention provides novelcompounds of formula (I), wherein: A is selected from

[0114] t is selected from 0, 1, and 2.

[0115] [4] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0116] R¹⁷ is selected from H; and

[0117] R¹⁸ is selected from H.

[0118] [5] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0119] A is selected from

[0120] [6] In another, the present invention provides novel compounds offormula (I) wherein:

[0121] G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, and—SO₂R³, —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,C(═C(CN)₂)NR²R³, and

[0122] [7]. In another embodiment, the present invention provides novelcompounds of formula (1), wherein:

[0123] G is selected from —C(O)NR²R³, ²³C(═NR^(1a))NR²R³, C(═CHCN)NR²R³,C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³;

[0124] [8] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0125] R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

[0126] R^(16a) and R^(16a)′, at each occurrence, are selected from H,methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with0-2 R^(16e);

[0127] R^(16e) at each occurrence, is selected from methyl, ethyl, Cl,F, Br, I, CN, CF₃, and OCH₃;

[0128] R^(16f), at each occurrence, is selected from H; and

[0129] r is selected from 0, 1, and 2.

[0130] [9] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0131] R³ is selected from a (CR³′R³″)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R¹⁵ and a (CR³′CR³″)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, subsitutedwith 0-2 R¹⁵;

[0132] R³′ and R³″, at each occurrence, are selected from H;

[0133] R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15f)R^(15f), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d),(CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

[0134] R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;

[0135] R^(15a) and R^(15a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

[0136] R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and(CH₂)_(r)-5-6 membered heterocyclic system containing 1-2 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); and

[0137] R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,Br, I, CN, (CF₂)_(r)CF₃, and OH.

[0138] [10] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0139] G is selected from

[0140] [11] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0141] R¹ is selected from H;

[0142] both X¹ and X² cannot be C; and

[0143] Z² is selected from NR¹′, O, and S.

[0144] [12] In a further embodiment, the present inveniton providesnovel compounds of formula (I), wherein:

[0145] R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

[0146] R^(16a) and R^(16a)′, at each occurrence, are selected from H,methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with0-2 R^(16e);

[0147] R^(16e), at each occurrence, is selected from methyl, ethyl, Cl,F, Br, I, CN, CF₃, and OCH₃;

[0148] R^(16f), at each occurrence, is selected from H; and

[0149] r is selected from 0, 1, and 2.

[0150] [13] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0151] R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15f)R^(15f), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d),(CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing ₁-₄ heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e);

[0152] R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;

[0153] R^(15a) and R^(15a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

[0154] R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and(CH₂)_(r)-5-6 membered heterocyclic system containing 1-2 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); and

[0155] R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,Br, I, CN, (CF₂)_(r)CF₃, and OH.

[0156] [14] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0157] A is selected from

[0158] v is selected from 0 and 1.

[0159] [15] In another embodiment, the present invention provides novelcompounds of formula (I) wherein:

[0160] G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, and—SO₂R³, —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,C(═C(CN)₂)NR²R³, and

[0161] [16]. In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0162] G is selected from —C(O)NR²R³,²³ C(═NR^(1a))NR²R³, C(═CHCN)NR²R³,C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³.

[0163] [17] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0164] R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

[0165] R^(16a) and R^(16a), at each occurrence, are selected from H,methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with0-2 R^(16e);

[0166] R^(16e), at each occurrence, is selected from methyl, ethyl, Cl,F, Br, I, CN, CF₃, and OCH₃;

[0167] R^(16f), at each occurrence, is selected from H; and

[0168] r is selected from 0, 1, and 2.

[0169] [18] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0170] R³ is selected from a (CR³′R³″)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R¹⁵ and a (CR³′CR³″)_(r)-⁵-¹⁰ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, subsitutedwith 0-2 R¹⁵

[0171] R³′ and R³″, at each occurrence, are selected from H;

[0172] R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR )_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

[0173] R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;

[0174] R^(15a) and R^(15a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

[0175] R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and(CH₂)_(r)-5-6 membered heterocyclic system containing 1-2 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); and

[0176] R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,Br, I, CN, (CF₂)_(r)CF₃, and OH.

[0177] [19] In a further embodiment, the prsent invention provides novelcompounds of formula (I), wherein:

[0178] G is selected from ,

[0179] [20] In a further embodiment, the present invention providesnovel compounds of formula (I), wherein:

[0180] R¹ is H;

[0181] both X¹ and x² cannot be C; and

[0182] Z² is selected from NR¹′, O, and S.

[0183] [21] In a further embodiment, the present inveniton providesnovel compounds of formula (I), wherein:

[0184] R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

[0185] R^(16a) and R^(16a)′, at each occurrence, are selected from H,methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with0-2 R^(16e);

[0186] R^(16e), at each occurrence, is selected from methyl, ethyl, Cl,F, Br, I, CN, CF₃, and OCH₃;

[0187] R^(16f), at each occurrence, is selected from H; and

[0188] r is selected from 0, 1, and 2.

[0189] [22] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0190] R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

[0191] R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;

[0192] R^(15a) and R^(15a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

[0193] R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and(CH₂)_(r)-5-6 membered heterocyclic system containing 1-2 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); and

[0194] R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,Br, I, CN, (CF₂)_(r)CF₃, and OH.

[0195] [23] In a further embodiment, the present invention providesnovel compounds of formula (I), wherein the compound of formula I isselected from:

[0196]N-(3-acetylphenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride;

[0197]N-(3-acetylphenyl)-N′-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride;

[0198]N-(3-cyanophenyl)-N′-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)1-cyclohexyl]urea trifluoroacetate;

[0199]N-(3-cyanophenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureatrifluoroacetate;

[0200]N-(3-cyanophenyl)-N′-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;

[0201]N-(3-cyanophenyl)-N′-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;

[0202]N-(3-acetylphenyl)-N′-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;

[0203]N-(3-acetylphenyl)-N′-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;

[0204]N-(3-acetylphenyl)-N′-[(2R)-2-[[(3R)1-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0205]N-(3-acetylphenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0206]N-(3-acetylphenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0207]N-(3-acetylphenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0208]N-(4-fluorophenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0209]N-(4-fluorophenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0210]N-(4-fluorophenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0211]N-(4-fluorophenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;

[0212]N-(3-acetylphenyl)-N′-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)urea;

[0213]N-(3-acetylphenyl)-N′-({(2S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;

[0214]N-(3-acetylphenyl)-N′-({(2S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;

[0215]N-(3-acetylphenyl)-N′-({(2R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;

[0216]N-(3-acetylphenyl)-N′-({(2R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;

[0217]N-(3-acetylphenyl)-N′-{(3R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;

[0218]N-(3-acetylphenyl)-N′-{(3R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;

[0219]N-(3-acetylphenyl)-N′-{(3S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;and

[0220]N-(3-acetylphenyl)-N′-{(3S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.

[0221] [24] In a third embodiment, the present invention provides apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention.

[0222] [25] In a fourth embodiment, the present invention provides amethod for modulation of chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compounds of the present invention.

[0223] [26] In another embodiment, the present invention provides amethod for treating or preventing inflammatory diseases, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compounds of the present invention.

[0224] [27] In another embodiment, the present invention provides amethod for treating-or preventing asthma, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention.

[0225] In another embodiment, G is selected from —C(O)R³, —C(O)NR²R³,—C(O)OR³, —SO₂NR²R³, —SO₂R³, —C(═S)NR²R³, C(═NR^(1a))NR²R³,C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, C(═C(CN)₂)NR²R³, and

[0226] In another embodiment, G is selected from —C(O)NR²R³,C(═CHCN)NR²R³, C(═CHNO₂)NR²R³ ₁ and C(═C(CN)₂)NR²R³.

[0227] In another embodiment, G is selected from —C(O)NR²R³.

[0228] In another embodiment, G is selected from

[0229] In another embodiment, R¹, R¹′, and R² are equal to H.

[0230] In another embodiment, R³ is selected from a (CR³′R³″)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R¹⁵ and a (CR³′CR³″)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, subtituted with 0-3 R¹⁵.

[0231] In another embodiment, R³ is selected from a (CR³′R³″)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R¹⁵.

[0232] In another embodiment, R³ is phenyl substitued with 0-2 R¹⁵.

[0233] In another embodiment, R⁴ is absent.

[0234] In another embodiment, R¹⁵, at each occurrence, is selected fromC₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e).

[0235] The invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention also encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment to describe additional embodiments of the present invention.Furthermore, any elements of an embodiment are meant to be combined withany and all other elements from any of the embodiments to describeadditional embodiments.

[0236] Definitions

[0237] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Many geometric isomers of olefins, C═N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

[0238] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., =O), then 2 hydrogens on the atom arereplaced.

[0239] The present invention is intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogeninclude-tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0240] When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up, to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0241] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0242] As used herein, “C₁₋₈ alkyl” is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₁₀ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups.,“Alkenyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more unsaturated carbon-carbonbonds which may occur in any stable point along the chain, such asethenyl, propenyl, and the like. C₂₋₁₀ alkenyl, is intended to includeC₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkenyl groups. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C_(5,) C₆, C₇, C₈, C₉ , and C₁₀alkoxy groups. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,n-pentoxy, and s-pentoxy. “Alkynyl” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl, propynyl, and the like. C₂₋₁₀alkynyl, is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀alkynyl groups. “C₃₋₆ cycloalkyl” is intended to include saturated ringgroups having the specified number of carbon atoms in the ring,including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C₇cycloalkyl. C₃₋₇ cycloalkyl, is intended to include C₃, C₄, C₅, C₆, andC₇ cycloalkyl groups.

[0243] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, and iodo; and “haloalkyl” is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups, for exampleCF₃, having the specified number of carbon atoms, substituted with 1 ormore halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

[0244] As used herein, the term “5-6-membered cyclic ketal” is intendedto mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxaneand their derivatives.

[0245] As used herein, “carbocycle” or “carbocyclic residue” is intendedto mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of whichmay be saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

[0246] As used herein, the term “heterocycle” or “heterocyclic system”is intended to mean a stable 4, 5, 6, or 7-membered monocyclic orbicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated (aromatic), and whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O and S and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom which results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Ifspecifically noted, a nitrogen in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. As used herein, the term “aromatic heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O and S.

[0247] Examples of heterocycles include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl.,oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl,piperonyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocyclesinclude, but are not limited to, pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

[0248] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[0249] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[0250] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0251] Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc . . . ) the compounds of the present invention may be delivered inprodrug form. Thus, the present invention is intended to cover prodrugsof the presently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

[0252] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. Only stable compounds are contemplated bythe present invention.

[0253] The term “therapeutically effective amount” of a compound of thisinvention means an amount alone or in combination with other activeingredients or an amount the combination of compounds claimed effectiveto modulate chemokine receptor activity or treat the symptoms of asthmaor an allergic disorder in a host.

[0254] Synthesis

[0255] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below. All references cited hereinare incorporated in their entirety by reference.

[0256] The novel compounds of Formula I may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One skilled in the art of organic synthesis understands that thefunctionality present on various portions of the edict molecule must becompatible with the reagents and reactions proposed. Not all compoundsof Formula I falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents that are compatible with the reactionconditions will be readily apparent to one skilled in the art andalternate methods must be used. It will also be recognized that anothermajor consideration in the planning of any synthetic route in this fieldis the judicious choice of the protecting group used for the protectionof the reactive functional groups present in the compounds described inthis invention. An authoritative account describing the manyalternatives to the trained practitioner is Greene and Wuts (ProtectiveGroups in Organic Chemistry, Wiley and Sons, 1991).

[0257] Compounds of Formula I may be prepared as shown in Scheme 1.Compounds in which D is a bond, O or NR¹ may be synthesized by reactingFormula II with Formula III, wherein Z is a good leaving such as but notlimited to Cl, Br, or imidazole, in the presence of a base such as, butnot limited to, triethylamine or pyridine. Alternatively, Formula II maybe reacted with an isocyanate of Formula V to provide compounds ofFormula I where G is CONHR³. Alternatively, Formula II may be reactedwith Formula IV, wherein Z is a good leaving group such as but notlimited to Cl, Br, or imidazole, in the presence of a base such as, butnot limited to, triethylamine or pyridine to provide compounds ofFormula I where G is SO₂R³. Alternatively, Formula II may be reactedwith Formulas VI, VII, or VIII wherein Z is a good leaving group such asbut not limited to ethoxide, phenoxide, or methylsulfide to providecompounds of Formula I according to procedures described in Hoffman,et.al. J. Med. Chem. 1983, 26, 140 and references therein.

[0258] Alternatively, compounds of Formula I can be synthesized bycoupling compounds of Formula II with halogenated heterocycles ofFormula IX as described in Scheme 2. It is understood that the chemistryis shown for only one heterocycle and that similar transformations maybe preformed on other halogenated heterocycles. This procedureessentially follows the general procedures of Hong, Y. et. al., Tet.Lett. 1997, 38, 5607 and references therein, with minor modificationdepending on the Formula IX which should be readily recognized by oneskilled in the art. The reaction can be preformed in an inert solventsuch as, but not limited to, toluene at room temperature to the refluxtemperature of the solvent with a Pd-catalyst such as Pd2(dba)3 and abase such as sodium t-butoxide. The halogenated heterocycles that arenot commercial available can be synthesized by methods known in the artand are exemplified by, but not limited to, Zou. R., J. Med Chem. 1997,40, 802.

[0259] Compounds of Formula II, where R¹ is not hydrogen, may beprepared by procedures depicted in Scheme 3. Reductive alkylation ofFormula X with an aldehyde or ketone is carried out under conditionsknown in the art, for example, catalytic hydrogenation with hydrogen inthe presence of palladium or platinum or with reducing agents,such assodium triacetoxyborohydride. Alternatively, a similar transformationcan be accomplished with an alkylating agent R¹Z where Z is a halide(halide=Cl, Br, I), mesylate, tosylate, triflate, etc. in the presenceof a base such as triethylamine, pyridine, etc. in acetonitrile, DMF,DMSO, etc. at room temperature to reflux temperature of the solvent.

[0260] Compounds of Formula X, where R⁴ is not hydrogen, may be preparedby procedures depicted in Scheme 4. Reductive alkylation of Formula XIwith an aldehyde or ketone is carried out under conditions known in theart, for example, catalytic hydrogenation with hydrogen in the presenceof palladium or platinum or with reducing agents such as sodiumtriacetoxyborohydride. Alternatively, a similar transformation can beaccomplished with an alkylating agent R⁴Z where Z is a halide(halide=Cl, Br, I), mesylate, tosylate, triflate, etc. in the presenceof a base such as triethylamine, pyridine, etc. in acetonitrile, DMF,DMSO, etc. at room temperature to reflux temperature of the solvent. Theprotecting group (P) can then be removed using the appropriate reagents,well familiar to one skilled in the art, and typical examples may befound in Greene, T and Wuts, P. G. M., Protecting Groups in OrganicSynthesis, John Wiley & Sons, Inc., New York, NY, 1991 and referencestherein, to provide intermediates of Formula X.

[0261] Compounds of Formula X, where R⁴ is hydrogen, or Formula XI maybe prepared by procedures depicted in Scheme 5. Reductive alkylation ofFormula XIII with a cyclic ketone of Formula XII can be carried outunder conditions known in the art, for example, catalytic hydrogenationwith hydrogen in the presence of palladium or platinum or with reducingagents such as sodium triacetoxyborohydride. Compounds of Formula XIIIthat are not commercially available can be synthesized by methods knownin the art and are exemplified by, but not limited to, Guan et. al.,Synlett 1999, 426, Skarzewski and Gupta Tetrahedron: Asymmetry, 1997, 8,1861, Bitha, and Lin, J. Heterocycl. Chem. 1988, 25, 1035, Ohba et. al.,Agric. Biol. Chem. 1974, 38, 2431, and Toftlund, and Pedersen, ActaChem. Scand., 1972, 26, 4019.

[0262] Compounds of Formula XII may be prepared by procedures depictedin Scheme 6. This procedure essentially follows the general protocols ofMitra and Joshi, Synth. Commun., (1988), 18, 2259 and referencestherein, with minor modification depending on R⁵ which should be readilyrecognized by one skilled in the art. The cycloalkenones can be treatedwith grinard reagents in the presence of copper chloride to incorporateR⁵ to produce compounds of Formula XII. Alternatively, monoprotectedcyclic diketones can be treated under wittig reaction conditions, wellknown to one skilled in the art, and then hydrogenated and deprotectedto produce compounds of Formula XII. Other methods for producingcompounds of Formula XII can be found in the reference Lednicer et.al.,J. Med. Chem. 1972, 15, 1239.

[0263] The compounds of this invention and their preparation can beunderstood further by the following working examples, which do notconstitute a limitation of the invention.

EXAMPLES Example 1

[0264] Preparation ofN-(3-acetylphenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride.

[0265] Part A. Preparation of8-[(4-fluorophenyl)methylene]-1,4-dioxaspiro[4.5]decane.

[0266] To a stirring solution of 4-fluorophenylmethyltriphenylphosphonium chloride (39 g, 96 mmol, Lancaster) in 500 mL ofdry THF at −78° C. was added 1 M potassium t-butoxide in THF (106 mL,106 mmol, Aldrich). The reaction was stirred for 30 min and then warmedto 0° C. The reaction was stirred for 30 min and then1,4-cyclohexanedione mono-ethylene ketal (15.0 g, 96 mmol, Aldrich) wasadded. After 30 min, the reaction was warmed to room temperature andallowed to stir overnight. The reaction was heated to reflux for 4 h andthen cooled to room temperature. The reaction was quenched withsaturated ammonium chloride (500 mL) and ethyl acetate (500 mL). Theorganic layer was separated, washed with brine, dried over sodiumsulfate, and conc in vacuo to a white solid. The solid was purified byflash chromatography (SiO2, 19:1 hexanes:ethyl acetate) to yield 18.9 gof a colorless oil. MS (ESI) 251 (M+H).

[0267] Part B: Preparation of8-[(4-fluorophenyl)methyl]-1,4-dioxaspiro[4.5]decane.

[0268] To a stirring degassed solution of8-[(4-fluorophenyl)methylene]-1,4-dioxaspiro[4.5]decane (18.9 g, 76mmol) and 10% palladium on carbon (3.8 g, Aldrich) in 500 mL of ethylacetate was added 40 psi of hydrogen gas. The reaction was stirred for2.5 h and then filtered through a pad of silica gel. The silica gel waswashed with ethyl acetate (300 mL). The organic layers were combined andconc in vacuo to a colorless oil yielding 18.0 g. MS (ESI) 253 (M+H).

[0269] Part C. Preparation of 4-[(4-fluorophenyl)methyl]-cyclohexanone.

[0270] To a stirring solution of8-[(4-fluorophenyl)methyl]-1,4-dioxaspiro[4.5]decane (18 g, 72 mmol) in100 mL of THF was added 1 M hydrogen chloride in water (70 mL) followedby conc hydrogen chloride (50 mL). The reaction was heated to reflux for5 h and then cooled to room temperature. The reaction was conc in vacuoto 120 mL and then extracted with ethyl acetate (3×100 mL). The organiclayers were combined, washed with sat sodium bicarbonate, brine, driedover sodium sulfate, and conc in vacuo to a colorless oil. The oil waspurified by flash chromatography (SiO2, 10:1 hexanes:ethyl acetate) toyield 9.6 g of a colorless oil. MS (ESI) 207 (M+H).

[0271] Part D. Preparation(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-amino-cyclohexaneditrifluoroacetate and(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-amino-cyclohexaneditrifluoroacetate.

[0272] To a stirring solution of4-[(4-fluorophenyl)methyl]-cyclohexanone (110 mg, 0.53 mmol) and (1R,2R)-1,2-diaminocyclohexane (76 mg, 0.66 mmol, Aldrich) in 10 mL ofmethylene chloride was added sodium triacetoxyborohydride (212 mg, 1mmol, Aldrich). The reaction was stirred for 16 h and then quenched bythe addition of 2N sodium hydroxide (5 mL). The reaction was extractedwith ethyl acetate (3×10 mL). The organic layers were combined, driedover magnesium sulfate, and conc in vacuo to a yellow oil. The oil waspurified by HPLC (C18, 90% water with 0.1% TFA/10% acetonitrile to 10%water with 0.1% TFA/90% acetonitrile) to yield 210 g of a white solid.MS (ESI) 305 (M-2TFA).

[0273] Part E. PreparationN-(3-acetylphenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride.

[0274] To a stirring solution of(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-amino-cyclohexaneditrifluoroacetate and(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-amino-cyclohexaneditrifluoroacetate (80 mg, 0.15 mmol) and triethylamine (61 mg, 0.6mmol, Aldrich) in 3 mL of dry THF was added 3-acetylphenyl isocyanate(24 mg, 0.15 mmol, Aldrich). The reaction was stirred for 30 min andthen quenched by the addition of methanol (1 mL). The reaction was concin vacuo to a yellow oil. The oil was purified radial chromatography(SiO2, ethyl acetate with 3% triethylamine) to yield a colorless oil.The oil was dissolved in ethyl ether and treated with 1 equivalent of 1Mhydrochloric acid in ethyl ether. The solution was conc in vacuo to awhite solid. The solid was dissolved in 1:1 acetonitrile and water andthen lyophilized to yield 33 mg of a white solid. MS (ESI) 466 (M-Cl).

Example 2

[0275] Preparation ofN-(3-acetylphenyl)-N′-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride.

[0276] The compound was isolated from the purification step of Example1, Part E and converted to the HCl salt according to procedures in StepE. MS (ESI) 466 (M-Cl).

Example 3

[0277] Preparation ofN-(3-cyanophenyl)-N′-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureatrifluoroacetate andN-(3-cyanophenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureatrifluoroacetate.

[0278] Prepared according to procedures described in Example 1 withmodification at Step E. The compound was purified by HPLC (C18, 90%water with 0.1% TFA/10% acetonitrile to 10% water with 0.1% TFA/90%acetonitrile) to yield a white solid. MS (ESI) 449 (M-TFA).

Example 4

[0279] Preparation ofN-(3-cyanophenyl)-N′-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate andN-(3-cyanophenyl)-N′-[(2S)-2;-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate.

[0280] Prepared according to procedures described in Example 3 withmodification at Step E. MS (ESI) 449 (M-TFA).

Example 5

[0281] Preparation ofN-(3-acetylphenyl)-N′-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate andN-(3-acetylphenyl)-N′-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate.

[0282] Prepared according to procedures described in Example 3 withmodification at Step E. MS (ESI),449 (M-TFA).

Example 6

[0283] Preparation ofN-(3-acetylphenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0284] Prepared according to procedures described in Example 1 withmodification at Step A in which 3-(4-fluorophenyl)-methylcyclohexanone,prepared according to procedures published by Mitra and Joshi, Synth.Comm. 1988, 18, 2559 and separated into the S and R enantiomers by HPLC(Chiralpak AD, ethanol), was substituted for4-(4-fluorophenyl)methylcyclohexanone and the products were notconverted to the hydrochloride salts. The. MS (ESI) 466 (M+H).

Example 7

[0285] Preparation ofN-(3-acetylphenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0286] Prepared according to procedures described in Example 6. MS (ESI)466 (M+H).

Example 8

[0287] Preparation ofN-(3-acetylphenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0288] Prepared according to procedures described in Example 6. MS (ESI)466 (M+H).

Example 9

[0289] Preparation ofN-(3-acetylphenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0290] Prepared according to procedures described in Example 6. MS (ESI)466 (M+H).

Example 10

[0291] Preparation ofN-(4-fluorophenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0292] Prepared according to procedures described in Example 6. MS (ESI)442 (M+H).

Example 11

[0293] Preparation ofN-(4-fluorophenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0294] Prepared according to procedures described in Example 6. MS (ESI)442 (M+H).

Example 12

[0295] Preparation ofN-(4-fluorophenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0296] Prepared according to procedures described in Example 6. MS (ESI)442 (M+H).

Example 13

[0297] Preparation ofN-(4-fluorophenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea.

[0298] Prepared according to procedures described in Example 6. MS (ESI)442 (M+H)

Example 14

[0299] Preparation ofN-(3-acetylphenyl)-N′-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)ureahydrochloride.

[0300] Part A. Preparation of (3S,4S)-3-aminotetrahydrofuran-4-ylcarbamic acid tert-butyl ester.

[0301] A flame-dried round bottom flask under nitrogen was charged withdry tetrahydrofuran (17 mL) and ((3S,4S)-tetrahydro-3,4-furandiamine(170 mg, 1.70 mmol) prepared according to the procedures of Skarzewski,J., et al. Tetrahedron: Asymmetry 1997, 8 (11), 1861. The solution wascooled to −78° C., and 2.5 M n-butyl lithium in hexanes (700 μL, 1.75mmol) was added. The resulting cloudy white suspension was warmed to 23°C., and the suspension became orange. After 10 min, tert-butyldicarbonate (371 mg, 1.70 mmol) was added in one portion. An additional100 mg-portion of tert-butyl dicarbonate was added after 10 min. Thereaction was then poured into saturated aqueous sodium chloride (50 mL),and the aqueous layer was washed with ethyl acetate (4×20 mL). Thecombined organic layers were dried over sodium sulfate, concentrated,and the resulting residue was purified by flash chromatography (5-10%methanol in dichloromethane) to yield the desired amine (90 mg, 26%) asa yellow oil. MS (ESI) 203 (M+H).

[0302] Part B. Preparation of tert-butyl(3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanylcarbamate.

[0303] To a flame-dried round bottom flask under nitrogen containing(3S,4S)-3-aminotetrahydrofuran-4-yl carbamic acid tert-butyl ester (90mg, 0.45 mmol) and 4-(4-fluorobenzyl)cyclohexanone (87 mg, 0.42 mmol) in1,2-dichloroethane (6 mL) was added sodium triacetoxyborohydride (191mg, 0.90 mmol). The resulting yellow mixture was stirred for 15 min andwas then poured into 1N aqueous hydrogen chloride (50 mL). The aqueouslayer was basified with 50% aqueous sodium hydroxide and washed withethyl acetate (4×20 mL). The combined organic layers were dried oversodium sulfate, concentrated, and the resulting residue was purified byflash chromatography (5% methanol in dichloromethane) to yield thedesired carbamic acid tert-butyl ester (94 mg, 53%) as a yellow oil. MS(ESI) 393 (M+H).

[0304] Part C. Preparation of(3S,4S)-N³-[4-(4-fluorobenzyl)cyclohexyl]tetrahydro-3,4-furandiaminedihydrochloride.

[0305] To tert-butyl(3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanylcarbamate(94 mg, 0.24 mmol) was added 4 M hydrogen chloride in dioxane (5 mL).Methanol (0.5 mL) was added to dissolve the resulting precipitate. Theresulting solution was concentrated after monitoring by electrospraymass spectrometry showed the reaction to be complete. Concentrationafforded the desired dihydrochloride (88 mg, 100%) as a white solid. MS(ESI) 293 (M−HCl₂).

[0306] Part D. Preparation ofN-(3-acetylphenyl)-N′-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)urea.

[0307] To a stirring solution of(3S,4S)-N³-[4-(4-fluorobenzyl)cyclohexyl]tetrahydro-3,4-furandiaminedihydrochloride (20 mg, 0.055 mmol) and triethylamine (100 μL, 0.72mmol) in dichloromethane (1 mL) was added 3-acetylphenyl isocyanate (7.1mg, 0.050 mmol). The resulting solution was immediately concentrated,and the resulting residue was purified by flash column chromatography(100% ethyl acetate then 5% triethylamine in ethyl acetate then 10%methanol in ethylacetate containing 5% triethylamine) to yield thedesired urea (15 mg, 60%) as an oily white solid. MS (ESI) 454 (M+H).

[0308] Part E. Preparation ofN-(3-acetylphenyl)-N′-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)ureahydrochloride.

[0309] To a stirring solution ofN-(3-acetylphenyl)-N′-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)urea(14 mg, 0.030 mmol) in dichloromethane (1 mL) was added 1.0 M hydrogenchloride in ether (300 μL, 0.030 mmol). After 5 min, the resultingsolution was concentrated and the residue lyopholized to afford thedesired hydrochloride (15 mg, 1000) as a white solid. MS (ESI) 454(M-Cl)

Example 15

[0310] Preparation ofN-(3-acetylphenyl)-N′-({(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea.

[0311] Part A. Preparation of{(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol and{(2S)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol.

[0312] To a stirring solution of 4-fluorophenylmethyl-cyclohexanone (300mg, 1.45 mmol, 1 eq.) and (S)-2-pyrrolidinemethanol (0.14 ml, 1.45 mmol,Aldrich) in 2 ml of 1,2-dichloroethane at 25° C. was added sodiumtriacetoxyborohydride (462 mg, 2.18 mmol, Aldrich). The reaction wasstirred for 5 hours then worked up by adding 10 ml of 1N NaOH thenextracting 3 times with chloroform. The organic was combined, dried overmagnesium sulfate, and concentrated in vacuo to obtain 400 mg of an oilas mixture of diastereomeric products. MS (ESI) detects 292 (M+H).

[0313] Part B. Preparation of(2S)-2-(chloromethyl)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidine

[0314] To a stirring solution of{(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol and{(2S)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol (390mg, 1.34 mmol) in 5 ml of methylene chloride at 25° C. under N₂ wasadded pyridine (0.22 ml, 2.75 mmol, EM Science) followed byp-toluenesulfonyl chloride (288 mg, 1.51 mmol, Aldrich). Worked up after16 hours by adding ethyl acetate then rinsing 3 times with sat'd sodiumbicarbonate followed by 1 time time with brine. The organic was driedover magnesium sulfate, and concentrated in vacuo to obtain an oil whichwas purified over silica gel in 100% ethyl acetate to yield 87 mg ofproduct. MS (ESI) detects 310 (M+H). The other isomer was isolated andused for example 16.

[0315] Part C. Preparation of(2S)-2-(azidomethyl)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidine

[0316] To a stirring solution of (2S)-2-(chloromethyl)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidine in 2 ml of DMSO (Aldrich)at 25° C. under N₂ was added sodium azide (28 mg, 2.90 mmol, Aldrich).The reaction was heated at 50° C. for 16 hours. Worked up by addingethyl acetate then rinsing 5 times with H2O. The organic was dried overmagnesium sulfate, and concentrated in vacuo to obtain 45 mg of an amberoil as product. MS (ESI) detects 317 (M+H).

[0317] Part D. Preparation of{(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanamine

[0318](2S)-2-(azidomethyl)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidine (45mg), 10% Pd/C (10 mg, Aldrich) and 5 ml of methanol were hydrogenatedfor 16 hours at 50 PSI. The reaction was filtered through fiberglassfilter paper under nitrogen. The filtrate was stripped to yield 58 mg ofan amber oil as product. MS (ESI) detects 291 (M+H).

[0319] Part E. Preparation ofN-(3-acetylphenyl)-N′-({(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea.

[0320] To a stirring solution of{(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanamine (58mg, 2 mmol) in 2 ml of THF at 25° C. under N₂ was added 3 acetylphenylisocyanate (32 mg, 2 mmol Aldrich). Worked up after 4 hours by strippingoff the THF then purifying over silica gel in 100% ethyl acetatefollowed by 4:1 chloroform/methanol. Obtained 11 mg of a white foam asproduct. MS (ESI) detects 452 (M+H).

Example 16

[0321] Preparation ofN-(3-acetylphenyl)-N′-({(2S)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea.

[0322] Prepared according to procedures described in Example 15. MS(ESI) detects 452 (M+H).

Example 17

[0323] Preparation ofN-(3-acetylphenyl)-N′-({(2R)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea.

[0324] Prepared according to procedures described in Example 15 exceptstarting with (R)-2-pyrrolidinemethanol. MS (ESI) detects 452 (M+H).

Example 18

[0325] Preparation ofN-(3-acetylphenyl)-N′-({(2R)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea.

[0326] Prepared according to procedures described in Example 15 exceptstarting with (R)-2-pyrrolidinemethanol. MS (ESI) detects 452 (M+H).

Example 19

[0327] Preparation ofN-(3-acetylphenyl)-N′-{(3R)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.

[0328] Prepared according to procedures described in Example 14 stepsb-d except starting with(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine. MS (ESI) detects 438(M+H).

Example 20

[0329] Preparation ofN-(3-acetylphenyl)-N′-{(3R)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.

[0330] Prepared according to procedures described in Example 14 stepsb-d except starting with(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine. MS (ESI) detects 438(M+H).

Example 21

[0331] Preparation ofN-(3-acetylphenyl)-N′-{(3S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.

[0332] Prepared according to procedures described in Example 14 stepsb-d except starting with(3S)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine. MS (ESI) detects 438(M+H).

Example 22

[0333] Preparation ofN-(3-acetylphenyl)-N′-{(3S)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.

[0334] Prepared according to procedures described in Example 14 stepsb-d except starting with(3S)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine. MS (ESI) detects 438(M+H).

[0335] The following table contains representative examples of thepresent invention. Each entry in the table is intended to be paired witheach formulae at the start of the table. For example, entry 1 in Table 1is intended to be-paired with a-r. TABLE 1

ENTRY R⁵ R³  1 4-F—Ph Ph  2 4-F—Ph 3-CN—Ph  3 4-F—Ph 3-COCH3—Ph  44-F—Ph 3-CO2Me—Ph  5 4-F—Ph 3-CO2Et—Ph  6 4-F—Ph 3-CO2H—Ph  7 4-F—Ph3-CONH2—Ph  8 4-F—Ph 3-CONHMe—Ph  9 4-F—Ph 3-F—Ph  10 4-F—Ph 3-Cl—Ph  114-F—Ph 3-Br—Ph  12 4-F—Ph 3-NO2—Ph  13 4-F—Ph 3-NH2—Ph  14 4-F—Ph3-NHMe—Ph  15 4-F—Ph 3-NMe2—Ph  16 4-F—Ph 3-NHCOCH3—Ph  17 4-F—Ph3-SO2NH2—Ph  18 4-F—Ph 3-SO2NHMe—Ph  19 4-F—Ph 3-CF3—Ph  20 4-F—Ph3-OCH3—Ph  21 4-F—Ph 3-OPh—Ph  22 4-F—Ph 3-OCF3—Ph  23 4-F—Ph 3-SCH3—Ph 24 4-F—Ph 3-SOCH3—Ph  25 4-F—Ph 3-SO2CH3—Ph  26 4-F—Ph 3-OH—Ph  274-F—Ph 3-CH2OH—Ph  28 4-F—Ph 3-CHOHCH3—Ph  29 4-F—Ph 3-COH(CH3)2—Ph  304-F—Ph 3-CHOHPh—Ph  31 4-F—Ph 3-CH3—Ph  32 4-F—Ph 3-C2H5—Ph  33 4-F—Ph3-iPr—Ph  34 4-F—Ph 3-tBu—Ph  35 4-F—Ph 3-Ph—Ph  36 4-F—Ph 3-CH2Ph—Ph 37 4-F—Ph 3-CH2CO2Me—Ph  38 4-F—Ph 3-(1-piperidinyl)-Ph  39 4-F—Ph3-(1-pyrrolidinyl)-Ph  40 4-F—Ph 3-(2-imidazolyl)-Ph  41 4-F—Ph3-(1-imidazolyl)-Ph  42 4-F—Ph 3-(2-thiazolyl)-Ph  43 4-F—Ph3-(3-pyrazolyl)-Ph  44 4-F—Ph 3-(1-pyrazolyl)-Ph  45 4-F—Ph3-(1-tetrazolyl)-Ph  46 4-F—Ph 3-(5-tetrazolyl)-Ph  47 4-F—Ph3-(2-pyridyl)-Ph  48 4-F—Ph 3-(2-thienyl)-Ph  49 4-F—Ph 3-(2-furanyl)-Ph 50 4-F—Ph 4-CN—Ph  51 4-F—Ph 4-COCH3—Ph  52 4-F—Ph 4-CO2Me—Ph  534-F—Ph 4-CO2Et—Ph  54 4-F—Ph 4-CO2H—Ph  55 4-F—Ph 4-CONH2—Ph  56 4-F—Ph4-CONHMe—Ph  57 4-F—Ph 4-CONHPh—Ph  58 4-F—Ph 4-NHCONH2—Ph  59 4-F—Ph4-F—Ph  60 4-F—Ph 4-Cl—Ph  61 4-F—Ph 4-Br—Ph  62 4-F—Ph 4-NO2—Ph  634-F—Ph 4-NH2—Ph  64 4-F—Ph 4-NHMe—Ph  65 4-F—Ph 4-NMe2—Ph  66 4-F—Ph4-NHCOCH3—Ph  67 4-F—Ph 4-SO2NH2—Ph  68 4-F—Ph 4-SO2NHMe—Ph  69 4-F—Ph4-CF3—Ph  70 4-F—Ph 4-OCH3—Ph  71 4-F—Ph 4-OPh—Ph  72 4-F—Ph 4-OCF3—Ph 73 4-F—Ph 4-SCH3—Ph  74 4-F—Ph 4-SOCH3—Ph  75 4-F—Ph 4-SO2CH3—Ph  764-F—Ph 4-OH—Ph  77 4-F—Ph 4-CH2OH—Ph  78 4-F—Ph 4-CHOHCH3—Ph  79 4-F—Ph4-COH(CH3)2—Ph  80 4-F—Ph 4-CH3—Ph  81 4-F—Ph 4-C2H5—Ph  82 4-F—Ph4-iPr—Ph  83 4-F—Ph 4-tBu—Ph  84 4-F—Ph 4-Ph—Ph  85 4-F—Ph 4-CH2Ph—Ph 86 4-F—Ph 4-CH2CO2Me—Ph  87 4-F—Ph 4-(1-piperidinyl)-Ph  88 4-F—Ph4-(1-pyrrolidinyl)-Ph  89 4-F—Ph 4-(2-imidazolyl)-Ph  90 4-F—Ph4-(1-imidazolyl)-Ph  91 4-F—Ph 4-(2-thiazolyl)-Ph  92 4-F—Ph4-(3-pyrazolyl)-Ph  93 4-F—Ph 4-(1-pyrazolyl)-Ph  94 4-F—Ph4-(1-tetrazolyl)-Ph  95 4-F—Ph 4-(5-tetrazolyl)-Ph  96 4-F—Ph4-(2-pyridyl)-Ph  97 4-F—Ph 4-(2-thienyl)-Ph  98 4-F—Ph 4-(2-furanyl)-Ph 99 4-F—Ph 2-CN—Ph 100 4-F—Ph 2-COCH3—Ph 101 4-F—Ph 2-CO2Me—Ph 1024-F—Ph 2-CO2Et—Ph 103 4-F—Ph 2-CO2H—Ph 104 4-F—Ph 2-CONH2—Ph 105 4-F—Ph2-CONHMe—Ph 106 4-F—Ph 2-F—Ph 107 4-F—Ph 2-Cl—Ph 108 4-F—Ph 2-Br—Ph 1094-F—Ph 2-NO2—Ph 110 4-F—Ph 2-NH2—Ph 111 4-F—Ph 2-NHMe—Ph 112 4-F—Ph2-NMe2—Ph 113 4-F—Ph 2-NHCOCH3—Ph 114 4-F—Ph 2-SO2NH2—Ph 115 4-F—Ph2-SO2NHMe—Ph 116 4-F—Ph 2-CF3—Ph 117 4-F—Ph 2-OCH3—Ph 118 4-F—Ph2-OPh—Ph 119 4-F—Ph 2-OCF3—Ph 120 4-F—Ph 2-SCH3—Ph 121 4-F—Ph 2-SOCH3—Ph122 4-F—Ph 2-SO2CH3—Ph 123 4-F—Ph 2-OH—Ph 124 4-F—Ph 2-CH2OH—Ph 1254-F—Ph 2-CHOHCH3—Ph 126 4-F—Ph 2-COH(CH3)2—Ph 127 4-F—Ph 2-CHOHPh—Ph 1284-F—Ph 2-CH3—Ph 129 4-F—Ph 2-C2H5—Ph 130 4-F—Ph 2-iPr—Ph 131 4-F—Ph2-tBu—Ph 132 4-F—Ph 2-Ph—Ph 133 4-F—Ph 2-CH2Ph—Ph 134 4-F—Ph2-CH2CO2Me—Ph 135 4-F—Ph 2-(1-piperidinyl)-Ph 136 4-F—Ph2-(1-pyrrolidinyl)-Ph 137 4-F—Ph 2-(2-imidazolyl)-Ph 138 4-F—Ph2-(1-imidazolyl)-Ph 139 4-F—Ph 2-(2-thiazolyl)-Ph 140 4-F—Ph2-(3-pyrazolyl)-Ph 141 4-F—Ph 2-(1-pyrazolyl)-Ph 142 4-F—Ph2-(1-tetrazolyl)-Ph 143 4-F—Ph 2-(5-tetrazolyl)-Ph 144 4-F—Ph2-(2-pyridyl)-Ph 145 4-F—Ph 2-(2-thienyl)-Ph 146 4-F—Ph 2-(2-furanyl)-Ph147 4-F—Ph 2,4-diF-Ph 148 4-F—Ph 2,5-diF-Ph 149 4-F—Ph 2,6-diF-Ph 1504-F—Ph 3,4-diF-Ph 151 4-F—Ph 3,5-diF-Ph 152 4-F—Ph 2,4-diCl—Ph 1534-F—Ph 2,5-diCl—Ph 154 4-F—Ph 2,6-diCl—Ph 155 4-F—Ph 3,4-diCl—Ph 1564-F—Ph 3,5-diCl—Ph 157 4-F—Ph 3,4-diCF3—Ph 158 4-F—Ph 3,5-diCF3—Ph 1594-F—Ph 5-Cl-2-MeO—Ph 160 4-F—Ph 5-Cl-2-Me—Ph 161 4-F—Ph 2-F-5-Me—Ph 1624-F—Ph 2-F-5-NO2—Ph 163 4-F—Ph 3,4-OCH2O—Ph 164 4-F—Ph 3,4-OCH2CH2O—Ph165 4-F—Ph 2-MeO-4-Me—Ph 166 4-F—Ph 2-MeO-5-Me—Ph 167 4-F—Ph 1-naphthyl168 4-F—Ph 2-naphthyl 169 4-F—Ph 2-thienyl 170 4-F—Ph 3-thienyl 1714-F—Ph 2-furanyl 172 4-F—Ph 3-furanyl 173 4-F—Ph 2-pyridyl 174 4-F—Ph3-pyridyl 175 4-F—Ph 4-pyridyl 176 4-F—Ph 2-indolyl 177 4-F—Ph 3-indolyl178 4-F—Ph 5-indolyl 179 4-F—Ph 6-indolyl 180 4-F—Ph 3-indazolyl 1814-F—Ph 5-indazolyl 182 4-F—Ph 6-indazolyl 183 4-F—Ph 2-imidazolyl 1844-F—Ph 3-pyrazolyl 185 4-F—Ph 2-thiazolyl 186 4-F—Ph 5-tetrazolyl 1874-F—Ph 2-benzimidazolyl 188 4-F—Ph 5-benzimidazolyl 189 4-F—Ph2-benzothiazolyl 190 4-F—Ph 5-benzothiazolyl 191 4-F—Ph 2-benzoxazolyl192 4-F—Ph 5-benzoxazolyl 193 2-F—Ph 3-CN—Ph 194 2-F—Ph 3-COCH3—Ph 1952-F—Ph 3-CO2Me—Ph 196 2-F—Ph 3-CO2Et—Ph 197 2-F—Ph 3-CO2H—Ph 198 2-F—Ph3-CONH2—Ph 199 2-F—Ph 3-F—Ph 200 2-F—Ph 3-Cl—Ph 201 2-F—Ph 3-NH2—Ph 2022-F—Ph 3-SO2NH2—Ph 203 2-F—Ph 3-CF3—Ph 204 2-F—Ph 3-OCH3—Ph 205 2-F—Ph3-OEt—Ph 206 2-F—Ph 3-OCF3—Ph 207 2-F—Ph 3-SO2CH3—Ph 208 2-F—Ph 3-OH—Ph209 2-F—Ph 3-CH3—Ph 210 2-F—Ph 3-C2H5—Ph 211 2-F—Ph 4-CN—Ph 212 2-F—Ph4-COCH3—Ph 213 2-F—Ph 4-CO2Me—Ph 214 2-F—Ph 4-CO2Et—Ph 215 2-F—Ph4-CO2H—Ph 216 2-F—Ph 4-CONH2—Ph 217 2-F—Ph 4-F—Ph 218 2-F—Ph 4-Cl—Ph 2192-F—Ph 4-NH2—Ph 220 2-F—Ph 4-SO2NH2—Ph 221 2-F—Ph 4-CF3—Ph 222 2-F—Ph4-OCH3—Ph 223 2-F—Ph 4-OEt—Ph 224 2-F—Ph 4-OCF3—Ph 225 2-F—Ph4-SO2CH3—Ph 226 2-F—Ph 4-OH—Ph 227 2-F—Ph 4-CH3—Ph 228 2-F—Ph 4-C2H5—Ph229 2-F—Ph 2,4-diF—Ph 230 2-F—Ph 2,5-diF—Ph 231 2-F—Ph 3,4-diF—Ph 2322-F—Ph 3,5-diF—Ph 233 2-F—Ph 2,4-diCl—Ph 234 2-F—Ph 2,5-diCl—Ph 2352-F—Ph 3,4-diCl—Ph 236 2-F—Ph 3,5-diCl—Ph 237 2-F—Ph 3,4-OCH2O—Ph 2382-F—Ph 3,4-OCH2CH2O—Ph 239 2-F—Ph 2-thienyl 240 2-F—Ph 2-furanyl 2412-F—Ph 2-pyridyl 242 2-F—Ph 4-pyridyl 243 2-F—Ph 2-imidazolyl 244 2-F—Ph3-pyrazolyl 245 2-F—Ph 2-thiazolyl 246 2-F—Ph 5-tetrazolyl 247 2-F—Ph1-adamantyl 248 2,4-diF—Ph 3-CN—Ph 249 2,4-diF—Ph 3-COCH3—Ph 2502,4-diF—Ph 3-CO2Me—Ph 251 2,4-diF—Ph 3-CO2Et—Ph 252 2,4-diF—Ph 3-CO2H—Ph253 2,4-diF—Ph 3-CONH2—Ph 254 2,4-diF—Ph 3-F—Ph 255 2,4-diF—Ph 3-Cl—Ph256 2,4-diF—Ph 3-NH2—Ph 257 2,4-diF—Ph 3-SO2NH2—Ph 258 2,4-diF—Ph3-CF3—Ph 259 2,4-diF—Ph 3-OCH3—Ph 260 2,4-diF—Ph 3-OEt—Ph 261 2,4-diF—Ph3-OCF3—Ph 262 2,4-diF—Ph 3-SO2CH3—Ph 263 2,4-diF—Ph 3-OH—Ph 2642,4-diF—Ph 3-CH3—Ph 265 2,4-diF—Ph 3-C2H5—Ph 266 2,4-diF—Ph 4-CN—Ph 2672,4-diF—Ph 4-COCH3—Ph 268 2,4-diF—Ph 4-CO2Me—Ph 269 2,4-diF—Ph4-CO2Et—Ph 270 2,4-diF—Ph 4-CO2H—Ph 271 2,4-diF—Ph 4-CONH2—Ph 2722,4-diF—Ph 4-F—Ph 273 2,4-diF—Ph 4-Cl—Ph 274 2,4-diF—Ph 4-NH2—Ph 2752,4-diF—Ph 4-SO2NH2—Ph 276 2,4-diF—Ph 4-CF3—Ph 277 2,4-diF—Ph 4-OCH3—Ph278 2,4-diF—Ph 4-OEt—Ph 279 2,4-diF—Ph 4-OCF3—Ph 280 2,4-diF—Ph4-SO2CH3—Ph 281 2,4-diF—Ph 4-OH—Ph 282 2,4-diF—Ph 4-CH3—Ph 2832,4-diF—Ph 4-C2H5—Ph 284 2,4-diF—Ph 2,4-diF—Ph 285 2,4-diF—Ph 2,5-diF—Ph286 2,4-diF—Ph 3,4-diF—Ph 287 2,4-diF—Ph 3,5-diF—Ph 288 2,4-diF—Ph2,4-diCl—Ph 289 2,4-diF—Ph 2,5-diCl—Ph 290 2,4-diF—Ph 3,4-diCl—Ph 2912,4-diF—Ph 3,5-diCl—Ph 292 2,4-diF—Ph 3,4-OCH2O—Ph 293 2,4-diF—Ph3,4-OCH2CH2O—Ph 294 2,4-diF—Ph 2-thienyl 295 2,4-diF—Ph 2-furanyl 2962,4-diF—Ph 2-pyridyl 297 2,4-diF—Ph 4-pyridyl 298 2,4-diF—Ph2-imidazolyl 299 2,4-diF—Ph 3-pyrazolyl 300 2,4-diF—Ph 2-thiazolyl 3012,4-diF—Ph 5-tetrazolyl 302 4-Cl—Ph Ph 303 4-Cl—Ph 3-CN—Ph 304 4-Cl—Ph3-COCH3—Ph 305 4-Cl—Ph 3-CO2Me—Ph 306 4-Cl—Ph 3-CO2Et—Ph 307 4-Cl—Ph3-CO2H—Ph 308 4-Cl—Ph 3-CONH2—Ph 309 4-Cl—Ph 3-CONHMe—Ph 310 4-Cl—Ph3-F—Ph 311 4-Cl—Ph 3-Cl—Ph 312 4-Cl—Ph 3-Br—Ph 313 4-Cl—Ph 3-NO2—Ph 3144-Cl—Ph 3-NH2—Ph 315 4-Cl—Ph 3-NHMe—Ph 316 4-Cl—Ph 3-NMe2—Ph 317 4-Cl—Ph3-NHCOCH3—Ph 318 4-Cl—Ph 3-SO2NH2—Ph 319 4-Cl—Ph 3-SO2NHMe—Ph 3204-Cl—Ph 3-CF3—Ph 321 4-Cl—Ph 3-OCH3—Ph 322 4-Cl—Ph 3-OPh—Ph 323 4-Cl—Ph3-OCF3—Ph 324 4-Cl—Ph 3-SCH3—Ph 325 4-Cl—Ph 3-SOCH3—Ph 326 4-Cl—Ph3-SO2CH3—Ph 327 4-Cl—Ph 3-OH—Ph 328 4-Cl—Ph 3-CH2OH—Ph 329 4-Cl—Ph3-CHOHCH3—Ph 330 4-Cl—Ph 3-COH(CH3)2—Ph 331 4-Cl—Ph 3-CHOHPh—Ph 3324-Cl—Ph 3-CH3—Ph 333 4-Cl—Ph 3-C2H5—Ph 334 4-Cl—Ph 3-iPr—Ph 335 4-Cl—Ph3-tBu—Ph 336 4-Cl—Ph 3-Ph—Ph 337 4-Cl—Ph 3-CH2Ph—Ph 338 4-Cl—Ph3-CH2CO2Me—Ph 339 4-Cl—Ph 3-(1-piperidinyl)-Ph 340 4-Cl—Ph3-(1-pyrrolidinyl)-Ph 341 4-Cl—Ph 3-(2-imidazolyl)-Ph 342 4-Cl—Ph3-(1-imidazolyl)-Ph 343 4-Cl—Ph 3-(2-thiazolyl)-Ph 344 4-Cl—Ph3-(3-pyrazolyl)-Ph 345 4-Cl—Ph 3-(1-pyrazolyl)-Ph 346 4-Cl—Ph3-(1-tetrazolyl)-Ph 347 4-Cl—Ph 3-(5-tetrazolyl)-Ph 348 4-Cl—Ph3-(2-pyridyl)-Ph 349 4-Cl—Ph 3-(2-thienyl)-Ph 350 4-Cl—Ph3-(2-furanyl)-Ph 351 4-Cl—Ph 4-CN—Ph 352 4-Cl—Ph 4-COCH3—Ph 353 4-Cl—Ph4-CO2Me—Ph 354 4-Cl—Ph 4-CO2Et—Ph 355 4-Cl—Ph 4-CO2H—Ph 356 4-Cl—Ph4-CONH2—Ph 357 4-Cl—Ph 4-CONHMe—Ph 358 4-Cl—Ph 4-CONHPh—Ph 359 4-Cl—Ph4-NHCONH2—Ph 360 4-Cl—Ph 4-F—Ph 361 4-Cl—Ph 4-Cl—Ph 362 4-Cl—Ph 4-Br—Ph363 4-Cl—Ph 4-NO2—Ph 364 4-Cl—Ph 4-NH2—Ph 365 4-Cl—Ph 4-NHMe—Ph 3664-Cl—Ph 4-NMe2—Ph 367 4-Cl—Ph 4-NHCOCH3—Ph 368 4-Cl—Ph 4-SO2NH2—Ph 3694-Cl—Ph 4-SO2NHMe—Ph 370 4-Cl—Ph 4-CF3—Ph 371 4-Cl—Ph 4-OCH3—Ph 3724-Cl—Ph 4-OPh—Ph 373 4-Cl—Ph 4-OCF3—Ph 374 4-Cl—Ph 4-SCH3—Ph 375 4-Cl—Ph4-SOCH3—Ph 376 4-Cl—Ph 4-SO2CH3—Ph 377 4-Cl—Ph 4-OH—Ph 378 4-Cl—Ph4-CH2OH—Ph 379 4-Cl—Ph 4-CHOHCH3—Ph 380 4-Cl—Ph 4-COH(CH3)2—Ph 3814-Cl—Ph 4-CH3—Ph 382 4-Cl—Ph 4-C2H5—Ph 383 4-Cl—Ph 4-iPr—Ph 384 4-Cl—Ph4-tBu—Ph 385 4-Cl—Ph 4-Ph—Ph 386 4-Cl—Ph 4-CH2Ph—Ph 387 4-Cl—Ph4-CH2CO2Me—Ph 388 4-Cl—Ph 4-(1-piperidinyl)-Ph 389 4-Cl—Ph4-(1-pyrrolidinyl)-Ph 390 4-Cl—Ph 4-(2-imidazolyl)-Ph 391 4-Cl—Ph4-(1-imidazolyl)-Ph 392 4-Cl—Ph 4-(2-thiazolyl)-Ph 393 4-Cl—Ph4-(3-pyrazolyl)-Ph 394 4-Cl—Ph 4-(1-pyrazolyl)-Ph 395 4-Cl—Ph4-(1-tetrazolyl)-Ph 396 4-Cl—Ph 4-(5-tetrazolyl)-Ph 397 4-Cl—Ph4-(2-pyridyl)-Ph 398 4-Cl—Ph 4-(2-thienyl)-Ph 399 4-Cl—Ph4-(2-furanyl)-Ph 400 4-Cl—Ph 2-CN—Ph 401 4-Cl—Ph 2-COCH3—Ph 402 4-Cl—Ph2-CO2Me—Ph 403 4-Cl—Ph 2-CO2Et—Ph 404 4-Cl—Ph 2-CO2H—Ph 405 4-Cl—Ph2-CONH2—Ph 406 4-Cl—Ph 2-CONHMe—Ph 407 4-Cl—Ph 2-F—Ph 408 4-Cl—Ph2-Cl—Ph 409 4-Cl—Ph 2-Br—Ph 410 4-Cl—Ph 2-NO2—Ph 411 4-Cl—Ph 2-NH2—Ph412 4-Cl—Ph 2-NHMe—Ph 413 4-Cl—Ph 2-NMe2—Ph 414 4-Cl—Ph 2-NHCOCH3—Ph 4154-Cl—Ph 2-SO2NH2—Ph 416 4-Cl—Ph 2-SO2NHMe—Ph 417 4-Cl—Ph 2-CF3—Ph 4184-Cl—Ph 2-OCH3—Ph 419 4-Cl—Ph 2-OPh—Ph 420 4-Cl—Ph 2-OCF3—Ph 421 4-Cl—Ph2-SCH3—Ph 422 4-Cl—Ph 2-SOCH3—Ph 423 4-Cl—Ph 2-SO2CH3—Ph 424 4-Cl—Ph2-OH—Ph 425 4-Cl—Ph 2-CH2OH—Ph 426 4-Cl—Ph 2-CHOHCH3—Ph 427 4-Cl—Ph2-COH(CH3)2—Ph 428 4-Cl—Ph 2-CHOHPh—Ph 429 4-Cl—Ph 2-CH3—Ph 430 4-Cl—Ph2-C2H5—Ph 431 4-Cl—Ph 2-iPr—Ph 432 4-Cl—Ph 2-tBu—Ph 433 4-Cl—Ph 2-Ph—Ph434 4-Cl—Ph 2-CH2Ph—Ph 435 4-Cl—Ph 2-CH2CO2Me—Ph 436 4-Cl—Ph2-(1-piperidinyl)-Ph 437 4-Cl—Ph 2-(1-pyrrolidinyl)-Ph 438 4-Cl—Ph2-(2-imidazolyl)-Ph 439 4-Cl—Ph 2-(1-imidazolyl)-Ph 440 4-Cl—Ph2-(2-thiazolyl)-Ph 441 4-Cl—Ph 2-(3-pyrazolyl)-Ph 442 4-Cl—Ph2-(1-pyrazolyl)-Ph 443 4-Cl—Ph 2-(1-tetrazolyl)-Ph 444 4-Cl—Ph2-(5-tetrazolyl)-Ph 445 4-Cl—Ph 2-(2-pyridyl)-Ph 446 4-Cl—Ph2-(2-thienyl)-Ph 447 4-Cl—Ph 2-(2-furanyl)-Ph 448 4-Cl—Ph 2,4-diF—Ph 4494-Cl—Ph 2,5-diF—Ph 450 4-Cl—Ph 2,6-diF—Ph 451 4-Cl—Ph 3,4-diF—Ph 4524-Cl—Ph 3,5-diF—Ph 453 4-Cl—Ph 2,4-diCl—Ph 454 4-Cl—Ph 2,5-diCl—Ph 4554-Cl—Ph 2,6-diCl—Ph 456 4-Cl—Ph 3,4-diCl—Ph 457 4-Cl—Ph 3,5-diCl—Ph 4584-Cl—Ph 3,4-diCF3—Ph 459 4-Cl—Ph 3,5-diCF3—Ph 460 4-Cl—Ph 5-Cl-2-MeO—Ph461 4-Cl—Ph 5-Cl-2-Me—Ph 462 4-Cl—Ph 2-F-5-Me—Ph 463 4-Cl—Ph2-F-5-NO2—Ph 464 4-Cl—Ph 3,4-OCH2O—Ph 465 4-Cl—Ph 3,4-OCH2CH2O—Ph 4664-Cl—Ph 2-MeO-4-Me—Ph 467 4-Cl—Ph 2-MeO-5-Me—Ph 468 4-Cl—Ph 1-naphthyl469 4-Cl—Ph 2-naphthyl 470 4-Cl—Ph 2-thienyl 471 4-Cl—Ph 3-thienyl 4724-Cl—Ph 2-furanyl 473 4-Cl—Ph 3-furanyl 474 4-Cl—Ph 2-pyridyl 4754-Cl—Ph 3-pyridyl 476 4-Cl—Ph 4-pyridyl 477 4-Cl—Ph 2-indolyl 4784-Cl—Ph 3-indolyl 479 4-Cl—Ph 5-indolyl 480 4-Cl—Ph 6-indolyl 4814-Cl—Ph 3-indazolyl 482 4-Cl—Ph 5-indazolyl 483 4-Cl—Ph 6-indazolyl 4844-Cl—Ph 2-imidazolyl 485 4-Cl—Ph 3-pyrazolyl 486 4-Cl—Ph 2-thiazolyl 4874-Cl—Ph 5-tetrazolyl 488 4-Cl—Ph 2-benzimidazolyl 489 4-Cl—Ph5-benzimidazolyl 490 4-Cl—Ph 2-benzothiazolyl 491 4-Cl—Ph5-benzothiazolyl 492 4-Cl—Ph 2-benzoxazolyl 493 4-Cl—Ph 5-benzoxazolyl494 2-Cl—Ph 3-CN—Ph 495 2-Cl—Ph 3-COCH3—Ph 496 2-Cl—Ph 3-CO2Me—Ph 4972-Cl—Ph 3-CO2Et—Ph 498 2-Cl—Ph 3-CO2H—Ph 499 2-Cl—Ph 3-CONH2—Ph 5002-Cl—Ph 3-F—Ph 501 2-Cl—Ph 3-Cl—Ph 502 2-Cl—Ph 3-NH2—Ph 503 2-Cl—Ph3-SO2NH2—Ph 504 2-Cl—Ph 3-CF3—Ph 505 2-Cl—Ph 3-OCH3—Ph 506 2-Cl—Ph3-OEt—Ph 507 2-Cl—Ph 3-OCF3—Ph 508 2-Cl—Ph 3-SO2CH3—Ph 509 2-Cl—Ph3-OH—Ph 510 2-Cl—Ph 3-CH3—Ph 511 2-Cl—Ph 3-C2H5—Ph 512 2-Cl—Ph 4-CN—Ph513 2-Cl—Ph 4-COCH3—Ph 514 2-Cl—Ph 4-CO2Me—Ph 515 2-Cl—Ph 4-CO2Et—Ph 5162-Cl—Ph 4-CO2H—Ph 517 2-Cl—Ph 4-CONH2—Ph 518 2-Cl—Ph 4-F—Ph 519 2-Cl—Ph4-Cl—Ph 520 2-Cl—Ph 4-NH2—Ph 521 2-Cl—Ph 4-SO2NH2—Ph 522 2-Cl—Ph4-CF3—Ph 523 2-Cl—Ph 4-OCH3—Ph 524 2-Cl—Ph 4-OEt—Ph 525 2-Cl—Ph4-OCF3—Ph 526 2-Cl—Ph 4-SO2CH3—Ph 527 2-Cl—Ph 4-OH—Ph 528 2-Cl—Ph4-CH3—Ph 529 2-Cl—Ph 4-C2H5—Ph 530 2-Cl—Ph 2,4-diF—Ph 531 2-Cl—Ph2,5-diF—Ph 532 2-Cl—Ph 3,4-diF—Ph 533 2-Cl—Ph 3,5-diF—Ph 534 2-Cl—Ph2,4-diCl—Ph 535 2-Cl—Ph 2,5-diCl—Ph 536 2-Cl—Ph 3,4-diCl—Ph 537 2-Cl—Ph3,5-diCl—Ph 538 2-Cl—Ph 3,4-OCH2O—Ph 539 2-Cl—Ph 3,4-OCH2CH2O—Ph 5402-Cl—Ph 2-thienyl 541 2-Cl—Ph 2-furanyl 542 2-Cl—Ph 2-pyridyl 5432-Cl—Ph 4-pyridyl 544 2-Cl—Ph 2-imidazolyl 545 2-Cl—Ph 3-pyrazolyl 5462-Cl—Ph 2-thiazolyl 547 2-Cl—Ph 5-tetrazolyl 548 2,4-diCl—Ph 3-CN—Ph 5492,4-diCl—Ph 3-COCH3—Ph 550 2,4-diCl—Ph 3-CO2Me—Ph 551 2,4-diCl—Ph3-CO2Et—Ph 552 2,4-diCl—Ph 3-CO2H—Ph 553 2,4-diCl—Ph 3-CONH2—Ph 5542,4-diCl—Ph 3-F—Ph 555 2,4-diCl—Ph 3-Cl—Ph 556 2,4-diCl—Ph 3-NH2—Ph 5572,4-diCl—Ph 3-SO2NH2—Ph 558 2,4-diCl—Ph 3-CF3—Ph 559 2,4-diCl—Ph3-OCH3—Ph 560 2,4-diCl—Ph 3-OEt—Ph 561 2,4-diCl—Ph 3-OEt—Ph 5622,4-diCl—Ph 3-SO2CH3—Ph 563 2,4-diCl—Ph 3-OH—Ph 564 2,4-diCl—Ph 3-CH3—Ph565 2,4-diCl—Ph 3-C2H5—Ph 566 2,4-diCl—Ph 4-CN—Ph 567 2,4-diCl—Ph4-COCH3—Ph 568 2,4-diCl—Ph 4-CO2Me—Ph 569 2,4-diCl—Ph 4-CO2Et—Ph 5702,4-diCl—Ph 4-CO2H—Ph 571 2,4-diCl—Ph 4-CONH2—Ph 572 2,4-diCl—Ph 4-F—Ph573 2,4-diCl—Ph 4-Cl—Ph 574 2,4-diCl—Ph 4-NH2—Ph 575 2,4-diCl—Ph4-SO2NH2—Ph 576 2,4-diCl—Ph 4-CF3—Ph 577 2,4-diCl—Ph 4-OCH3—Ph 5782,4-diCl—Ph 4-OEt—Ph 579 2,4-diCl—Ph 4-OCF3—Ph 580 2,4-diCl—Ph4-SO2CH3—Ph 581 2,4-diCl—Ph 4-OH—Ph 582 2,4-diCl—Ph 4-CH3—Ph 5832,4-diCl—Ph 4-C2H5—Ph 584 2,4-diCl—Ph 2,4-diF—Ph 585 2,4-diCl—Ph2,5-diF—Ph 586 2,4-diCl—Ph 3,4-diF—Ph 587 2,4-diCl—Ph 3,5-diF—Ph 5882,4-diCl—Ph 2,4-diCl—Ph 589 2,4-diCl—Ph 2,5-diCl—Ph 590 2,4-diCl—Ph3,4-diCl—Ph 591 2,4-diCl—Ph 3,5-diCl—Ph 592 2,4-diCl—Ph 3,4-OCH2O—Ph 5932,4-diCl—Ph 3,4-OCH2CH2O—Ph 594 2,4-diCl—Ph 2-thienyl 595 2,4-diCl—Ph2-furanyl 596 2,4-diCl—Ph 2-pyridyl 597 2,4-diCl—Ph 4-pyridyl 5982,4-diCl—Ph 2-imidazolyl 599 2,4-diCl—Ph 3-pyrazolyl 600 2,4-diCl—Ph2-thiazolyl 601 2,4-diCl—Ph 5-tetrazolyl 602 3-OCH3—Ph 3-CN—Ph 6033-OCH3—Ph 3-COCH3—Ph 604 3-OCH3—Ph 3-CO2Me—Ph 605 3-OCH3—Ph 3-CO2Et—Ph606 3-OCH3—Ph 3-CO2H—Ph 607 3-OCH3—Ph 3-CONH2—Ph 608 3-OCH3—Ph 3-F—Ph609 3-OCH3—Ph 3-Cl—Ph 610 3-OCH3—Ph 3-NH2—Ph 611 3-OCH3—Ph 3-SO2NH2—Ph612 3-OCH3—Ph 3-CF3—Ph 613 3-OCH3—Ph 3-OCH3—Ph 614 3-OCH3—Ph 3-OEt—Ph615 3-OCH3—Ph 3-OCF3—Ph 616 3-OCH3—Ph 3-SO2CH3—Ph 617 3-OCH3—Ph 3-OH—Ph618 3-OCH3—Ph 3-CH3—Ph 619 3-OCH3—Ph 3-C2H5—Ph 620 3-OCH3—Ph 4-CN—Ph 6213-OCH3—Ph 4-COCH3—Ph 622 3-OCH3—Ph 4-CO2Me—Ph 623 3-OCH3—Ph 4-CO2Et—Ph624 3-OCH3—Ph 4-CO2H—Ph 625 3-OCH3—Ph 4-CONH2—Ph 626 3-OCH3—Ph 4-F—Ph627 3-OCH3—Ph 4-Cl—Ph 628 3-OCH3—Ph 4-NH2—Ph 629 3-OCH3—Ph 4-SO2NH2—Ph630 3-OCH3—Ph 4-CF3—Ph 631 3-OCH3—Ph 4-OCH3—Ph 632 3-OCH3—Ph 4-OEt—Ph633 3-OCH3—Ph 4-OCF3—Ph 634 3-OCH3—Ph 4-SO2CH3—Ph 635 3-OCH3—Ph 4-OH—Ph636 3-OCH3—Ph 4-CH3—Ph 637 3-OCH3—Ph 4-C2H5—Ph 638 3-OCH3—Ph 2,4-diF—Ph639 3-OCH3—Ph 2,5-diF—Ph 640 3-OCH3—Ph 3,4-diF—Ph 641 3-OCH3—Ph3,5-diF—Ph 642 3-OCH3—Ph 2,4-diCl—Ph 643 3-OCH3—Ph 2,5-diCl—Ph 6443-OCH3—Ph 3,4-diCl—Ph 645 3-OCH3—Ph 3,5-diCl—Ph 646 3-OCH3—Ph3,4-OCH2O—Ph 647 3-OCH3—Ph 3,4-OCH2CH2O—Ph 648 3-OCH3—Ph 2-thienyl 6493-OCH3—Ph 2-furanyl 650 3-OCH3—Ph 2-pyridyl 651 3-OCH3—Ph 4-pyridyl 6523-OCH3—Ph 2-imidazolyl 653 3-OCH3—Ph 3-pyrazolyl 654 3-OCH3—Ph2-thiazolyl 655 3-OCH3—Ph 5-tetrazolyl 656 2-F—Ph 3,5-diCOCH3—Ph 6574-F—Ph 3,5-diCOCH3—Ph 658 2,4-diF—Ph 3,5-diCOCH3—Ph 659 2-Cl—Ph3,5-diCOCH3—Ph 660 4-Cl—Ph 3,5-diCOCH3—Ph 661 2,4-diCl—Ph 3,5-diCOCH3—Ph662 3-OCH3—Ph 3,5-diCOCH3—Ph

[0336] Utility

[0337] The utility of the compounds in accordance with the presentinvention as modulators of chemokine receptor activity may bedemonstrated by methodology known in the art, such as the assays forCCR-2 and CCR-3 ligand binding, as disclosed by Ponath et al., J. Exp.Med., 183, 2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100,1137-1143 (1997). Cell lines for expressing the receptor of interestinclude those naturally expressing the chemokine receptor, such as EOL-3or THP-1, those induced to express the chemokine receptor by theaddition of chemical or protein agents, such as HL-60 or AML14.3D10cells treated with, for example, butyric acid with interleukin-5present, or a cell engineered to express a recombinant chemokinereceptor, such as CHO or HEK-293. Finally, blood or tissue cells, forexample human peripheral blood eosinophils, isolated using methods asdescribed by Hansel et al., J. Immunol. Methods, 145, 105-110 (1991),can be utilized in such assays. In particular, the compound of thepresent invention have activity in binding to the CCR-3 receptor in theaforementioned assays. As used herein, “activity” is intended to mean acompound demonstrating an IC50 of 10 μM or lower in concentration whenmeasured in the aforementioned assays. Such a result is indicative ofthe intrinsic activity of the compounds as modulators of chemokinereceptor activity. A general binding protocol is described below.

[0338] CCR3-Receptor Binding Protocol

[0339] Millipore filter plates (#MABVN1250) are treated with 5 μg/mlprotamine in phosphate buffered saline, pH 7.2, for ten minutes at roomtemperature. Plates are washed three times with phosphate bufferedsaline and incubated with phosphate buffered saline for thirty minutesat room temperature. For binding, 50 μl of binding buffer (0.5% bovineserum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI1640 media) with or without a test concentration of a compound presentat a known concentration is combined with 50 μl of 125-I labeled humaneotaxin (to give a final concentration of 150 pM radioligand) and 50 μlof cell suspension in binding buffer containing 5×10⁵ total cells. Cellsused for such binding assays can include cell lines transfected with agene expressing CCR3 such as that described by Daugherty et al. (1996),isolated human eosinophils such as described by Hansel et al. (1991) orthe AML14.3D10 cell line after differentiation with butyric acid asdescribed by Tiffany et al. (1998). The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and plates washedthree times with binding buffer with 0.5M NaCl added. The plastic skirtis removed from the plate, the plate allowed to air dry, the wells punchout and CPM counted. The percent inhibition of binding is calculatedusing the total count obtained in the absence of any competing compoundor chemokine ligand and the background binding determined by addition of100 nM eotaxin in place of the test compound.

[0340] The utility of the compounds in accordance with the presentinvention as inhibitors of the migration of eosinophils or cell linesexpressing the chemokine receptors may be demonstrated by methodologyknown in the art, such as the chemotaxis assay disclosed by Bacon etal., Brit. J. Pharmacol., 95, 966-974 (1988). In particular, thecompound of the present invention have activity in inhibition of themigration of eosinophils in the aforementioned assays. As used herein,“activity” is intended to mean a compound demonstrating an IC50 of 10 μMor lower in concentration when measured in the aforementioned assays.Such a result is indicative of the intrinsic activity of the compoundsas modulators of chemokine receptor activity. A human eosinophilchemotaxis assay protocol is described below.

[0341] Human Eosinophil Chemotaxis Assay

[0342] Neuroprobe MBA96 96-well chemotaxis chambers with Neuroprobepolyvinylpyrrolidone-free polycarbonate PFD5 5-micron filters in placeare warmed in a 37° C. incubator prior to assay. Freshly isolated humaneosinophils, isolated according to a method such as that described byHansel et al. (1991), are suspended in RPMI 1640 with 0.1% bovine serumalbumin at 1×10⁶ cells/ml and warmed in a ₃₇° C. incubator prior toassay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovineserum albumin is warmed in a 37° C. incubator prior to assay. Theeosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or withouta dilution of a test compound that is at two fold the desired finalconcentration. These mixtures are warmed in a 37° C. incubator prior toassay. The filter is separated from the prewarmed Neuroprobe chemotaxischamber and the eotaxin/compound mixture is placed into a PolyfiltronicsMPC 96 well plate that has been placed in the bottom part of the NeuroProbe chemotaxis chamber. The approximate volume is 370 microliters andthere should be a positive meniscus after dispensing. The filter isreplaced above the,96 well plate, the rubber gasket is attached to thebottom of the upper chamber, and the chamber assembled. A 200 μl volumeof the cell suspension/compound mixture is added to the appropriatewells of the upper chamber. The upper chamber is covered with a platesealer, and the assembled unit placed in a 37° C. incubator for 45minutes. After incubation, the plate sealer is removed and all remainingcell suspension is aspirated off. The chamber is disassembled and, whileholding the filter by the sides at a 90-degree angle, unmigrated cellsare washed away using a gentle stream of phosphate buffered salinedispensed from a squirt bottle and then the filter wiped with a rubbertipped squeegee. The filter is allowed to completely dry and immersedcompletely in Wright Giemsa stain for 30-45 seconds. The filter isrinsed with distilled water for 7 minutes, rinsed once with waterbriefly, and allowed to dry. Migrated cells are enumerated bymicroscopy.

[0343] Mammalian chemokine receptors provide a target for interferingwith or promoting immune cell function in a mammal, such as a human.Compounds that inhibit or promote chemokine receptor function areparticularly useful for modulating immune cell function for therapeuticpurposes. Accordingly, the present invention is directed to compoundswhich are useful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

[0344] For example, an instant compound which inhibits one or morefunctions of a mammalian chemokine receptor (e.g., a human chemokinereceptor) may be administered to inhibit (i.e., reduce or prevent)inflammation or infectious disease. As a result, one or moreinflammatory process, such as leukocyte emigration, adhesion,chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatorymediator release, is inhibited. For example, eosinophilic infiltrationto inflammatory sites (e.g., in asthma or allergic rhinitis) can beinhibited according to the present method. In particular, the compoundof the following examples has activity in blocking the migration ofcells expressing the CCR-3 receptor using the appropriate chemokines inthe aforementioned assays. As used herein, “activity” is intended tomean a compound demonstrating an IC50 of 10 μM or lower in concentrationwhen measured in the aforementioned assays. Such a result is alsoindicative of the intrinsic activity of the compounds as modulators ofchemokine receptor activity.

[0345] Similarly, an instant compound which promotes one or morefunctions of the mammalian chemokine receptor (e.g., a human chemokine)as administered to stimulate (induce or enhance) an immune orinflammatory response, such as leukocyte emigration, adhesion,chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatorymediator release, resulting in the beneficial stimulation ofinflammatory processes. For example, eosinophils can be recruited tocombat parasitic infections. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for an instant compound which promotes one or morefunctions of the mammalian chemokine receptor if one contemplates thedelivery of sufficient compound to cause the loss of receptor expressionon cells through the induction of chemokine receptor internalization orthe delivery of compound in a manner that results in the misdirection ofthe migration of cells.

[0346] In addition to primates, such as humans, a variety of othermammals can be treated according to the method of the present invention.For instance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

[0347] Diseases or conditions of human or other species which can betreated with inhibitors of chemokine receptor function, include, but arenot limited to: inflammatory or allergic diseases and conditions,including respiratory allergic diseases such as asthma, allergicrhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with-rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and-inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

[0348] Diseases or conditions of humans or other species which can betreated with promoters of chemokine receptor function, include, but arenot limited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

[0349] In another aspect, the instant invention may be used to evaluatethe putative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

[0350] Combined therapy to prevent and treat inflammatory, infectiousand immunoregulatory disorders and diseases, including asthma andallergic diseases, as well as autoimmune pathologies such as rheumatoidarthritis and atherosclerosis, and those pathologies noted above isillustrated by the combination of the compounds of this invention andother compounds which are known for such utilities. For example, in thetreatment or prevention of inflammation, the present compounds may beused in conjunction with an anti-inflammatory or analgesic agent such asan opiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,a tumor necrosis factor inhibitor, an NMDA antagonist, an inhibitor ornitric oxide or an inhibitor of the synthesis of nitric oxide, anon-steroidal anti-inflammatory agent, a phosphodiesterase inhibitor, ora cytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) integrin antagonists such as those for selectins,ICAMs and VLA-4; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(Hi-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,.oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (1) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (O) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with an NSAID the weight ratio ofthe compound of the present invention to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

[0351] The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

[0352] Dosage and Formulation

[0353] The compounds of this invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0354] The dosage regimen for the compounds of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. A physician or veterinarian candetermine and prescribe the effective amount of the drug required toprevent, counter, or arrest the progress of the thromboembolic disorder.

[0355] By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

[0356] Compounds of this invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal skin patches. When administered in the form ofa transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen.

[0357] The compounds are typically administered in admixture withsuitable pharmaceutical diluents, excipients, or carriers (collectivelyreferred to herein as pharmaceutical carriers) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

[0358] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

[0359] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0360] Compounds of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0361] Dosage forms (pharmaceutical compositions) suitable foradministration may contain from about 1 milligram to about 100milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

[0362] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

[0363] Liquid dosage-forms for oral administration can contain coloringand flavoring to increase patient acceptance.

[0364] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

[0365] Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

[0366] Representative useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

[0367] Capsules

[0368] A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

[0369] Soft Gelatin Capsules

[0370] A mixture of active ingredient in a digestable oil such assoybean oil, cottonseed oil or olive oil may be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules should be washed and dried.

[0371] Tablets

[0372] Tablets may be prepared by-conventional procedures so that thedosage unit is 100 milligrams of active ingredient, 0.2 milligrams ofcolloidal silicon dioxide, 5 milligrams of magnesium stearate, 275milligrams of microcrystalline cellulose, 11 milligrams of starch and98.8 milligrams of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

[0373] Injectable

[0374] A parenteral composition suitable for administration by injectionmay be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution should be madeisotonic with sodium chloride and sterilized.

[0375] Suspension

[0376] An aqueous suspension can be prepared for oral administration sothat each 5 mL contain 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

[0377] Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

[0378] Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

[0379] Particularly when provided as a single dosage unit, the potentialexists for a chemical interaction between the combined activeingredients. For this reason, when the compound of Formula I and asecond therapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

[0380] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time by the same manner, will be readily apparent tothose skilled in the art, once armed with the present disclosure.

[0381] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is:
 1. A compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:A is selected from

G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, —SO₂R³,—C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,C(═C(CN)₂)NR²R³,

W, at each occurrence, is independently selected from C or N, providedat least two of W are C; X is selected from O, S, and NR¹⁹; X¹ and X²are independently selected from C and N; Z¹ is selected from C and N; Z²is selected from NR^(1a), O, S and C; R¹ and R² are independentlyselected from H, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a); R^(1a)is independently selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a);R^(a), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH, (CH₂)_(r)OR^(c), (CH₂)_(r)SH,(CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b), (CH₂)_(r)C(O)NR^(b)R^(b),(CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),(CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),(CH₂)_(r)S(O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),(CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl; R^(b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl; alternatively, R² and R³ join to form a 5, 6, or 7-memberedring substituted with 0-3 R^(a); R³ is selected from a(CR³′R³″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R¹⁵ and a(CR³′R³″)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵; R³′ andR³″, at each occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R⁴ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(a); alternatively, R⁴ joins with R⁸ orR¹¹ to form a pyrrolidine or piperidine ring system substituted with 0-3R^(4d); R⁴′ is absent, taken with the nitrogen to which it is attachedto form an N-oxide, or selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4a), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c); R^(4a) and R^(4a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R^(4b), at each occurrence, is selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, andphenyl; R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC¹⁵ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl; R^(4d), is selected fromH, C₁₋₆ alkyl, (CHR′)_(q)OH, (CHR′)_(q)OR^(7a), (CHR′)_(q)OC(O)R^(7b),(CHR′)_(q)OC(O)NHR^(7a); R⁵ is selected from a (CR⁵′R⁵″)_(t)—C₃₋₁₀_(³¹⁰) carbocyclic residue substituted with 0-5 R¹⁶¹⁶ and a(CR⁵′R⁵″)_(t)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶¹⁶; R⁵′⁵and R⁵″⁵, at each occurrence, are selected from H, C₁₋₆ _(¹⁶) alkyl,(CH₂₂)_(r)C₃₋₆ _(³⁶) cycloalkyl, and phenyl; R⁷, is selected from H,C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CHR′)_(q)OH, (CHR′)_(q)SH,(CHR′)_(q)OR^(7d), (CHR′)_(q)SR^(7d), (CHR′)_(q)NR^(7a)R^(7a)′,(CHR′)_(q)C(O)OH, (CHR′)_(r)C(O)R^(7b), (CHR′)_(q)C(O)NR^(7a)R^(7a)′,(CHR′)_(q)NR^(7a)C(O)R^(7a), (CHR′)_(q)NR^(7a)C(O)H,(CHR′)_(q)C(O)OR^(7a), (CHR′)_(q)OC(O)R^(7b), (CHR′)_(q)S(O)_(p)R^(7b),(CHR′)_(q)S(O)₂NR^(7a)R^(7a)′, (CHR′)_(q)NR⁷aS (O)₂R^(7b),(CHR′)_(q)NHC(O)NR^(7a)′R^(7a), (CHR′)_(q)NHC(O)OR^(7a),(CHR′)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(7c), and a (CHR′)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7c); R^(7a) and R^(7a)′, at each occurrence,are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(7e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b), (CH₂) _(r)C(O)NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted-with 0-3 R^(7e); R^(7d), at each occurrence,is selected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e),and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c); R^(7e), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, (CH₂)_(q)OH, OH, (CH₂)_(q)SH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(q)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected fromH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(8a); R^(8c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; alternatively, R⁷ and R⁸join to form C₃₋₇ cycloalkyl, or ═NR^(8b); R^(8b) is selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and (CH₂)_(r)-phenyl; R¹¹, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH,(CH₂)_(q)SH, (CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d),(CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂) _(q)NR^(11a)C(O)R^(11b),(CH₂)_(q)NR^(11a)C(O)NR^(11a)R^(11a), (CH₂)_(r)C(O)OR^(11a),(CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(11e), and a (CH₂)_(r)-5-⁶ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11d), at eachoccurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(11c); R^(11e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹⁵, ateach occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,(CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(15e); R^(15a) andR^(15a)′, at each occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(15e); and a (CH₂)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(15e); R^(15b), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); R^(15d), at each occurrence, is selected from C₃₋₈alkenyl, C₃₋₈ alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3R^(15e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(15e), and a (CH₂)_(r)5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e);R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(51f), and (CH₂)_(r)phenyl; R^(15f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR.)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)NHC(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S. substituted with 0-2 R^(16e);R^(16d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(16e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e), and a(CH₂)_(r)-5-⁶ membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(16e); R^(16e), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl; R^(16f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, andphenyl; R¹⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(17d), (CH₂)_(q)SR^(17d),(CH₂)_(q)NR^(17a)R^(17a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(17b),(CH₂)_(r)C(O)NR^(17a)R^(17a)′, (CH₂)_(q)NR^(17a)C(O)R^(17b),(CH₂)_(q)NR^(17a)C(O)H, (CH₂)_(r)C(O)OR^(17a), (CH₂)_(q)OC(O)R^(17b),(CH₂)_(q)S(O)_(p)R^(17b), (CH₂)_(q)S(O)₂NR^(17a)R^(17a)′,(CH₂)_(q)NR^(17a)S(O)₂R^(17b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(17c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(17c); R^(17a) and R^(17a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(17e), anda (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(17e); R^(17b), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(17e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(17e);R^(17c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(17f)R^(17f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(17b),(CH₂)_(r)C(O)NR^(17f)R^(17f), (CH₂)_(r)NR^(17f)C(O)R^(17a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(17b),(CH₂)_(r)C(═NR^(17f))NR^(17f)R^(17f), (CH₂)_(r)S(O)_(p)R^(17b),(CH₂)_(r)NHC(═NR^(17f))NR^(17f)R^(17f), (CH₂)_(r)S(O)₂NR^(17f)R^(17f),(CH₂)_(r)NR^(17f)S(O)₂R^(17b), and (CH₂)_(r)phenyl substituted with 0-3R^(17e); R^(17d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(17e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(17c); R^(17e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(17f)R^(17f), and(CH₂)_(r)phenyl; R^(17f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹⁸, is selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CHR′)_(q)OH, (CHR′)_(q)SH, (CHR )_(q)OR^(18d),(CHR′)_(q)SR^(18d), (CHR′)_(q)NR^(18a)R^(18a)′, (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)R^(18b), (CHR′)_(r)C(O)NR^(18a)R^(18a)′,(CHR′)_(q)NR^(18a)C(O)R^(18a), (CHR′)_(q)NR^(18a)C(O)H,(CHR′)_(r)C(O)OR^(18a), (CHR′)_(q)OC(O)R^(18b),(CHR′)_(q)S(O)_(p)R^(18b), (CHR′)_(q)S(O)₂NR^(18a)R^(18a)′,(CHR′)_(q)NR^(18a)S(O)₂R^(18b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(18c), and a (CHR′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(18c); R^(18a) and R^(18a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(18e), anda (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(18e); R^(18b), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(18e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(18e);R^(18c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(18f)R^(18f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(18b),(CH₂)_(r)C(O)NR^(18f)R^(18f), (CH₂)_(r)NR^(18f)C(O)R^(18a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(18b),(CH₂)_(r)C(═NR^(18f))NR^(18f)R^(18f), (CH₂)_(r)S(O)_(p)R^(18b),(CH₂)_(r)NHC(═NR^(18f))NR^(18f)R^(18f), (CH₂)_(r)S(O)₂NR^(18f)R^(18f),(CH₂)_(r)NR^(18f)S(O)₂R^(18b), and (CH₂)_(r)phenyl substituted with 0-3R^(18e); R^(18d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(18e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(18c); R^(18e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(18f)R^(18f), and(CH₂)_(r)phenyl; R^(18f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹⁹ is selected from C₁₋₈ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, —C(O)R^(19b), —C(O)NR^(19a)R^(19a),—C(O)OR^(19a), and —SO₂R^(19a), a (CHR′)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R¹⁶, and a (CHR′)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R¹⁶; R^(19a) is selected from C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, C₃₋₆ cycloalkyl, a (CR⁵′⁵R⁵″)_(t)—C₃₋₁₀ _(³¹⁰) carbocyclicresidue substituted with 0-5 R¹⁵¹⁶ and a (CR⁵′⁵R⁵″⁵)_(r)-5-10membered-heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R¹⁶¹⁶; R^(19b) is selected from H, C₁₋₈alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₆ cycloalkyl, a(CR⁵′R⁵″)_(t)—C₃₋₁₀ _(³¹⁰) carbocyclic residue substituted with 0-5R¹⁵¹⁶ and a (CR⁵′R⁵″)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶¹⁶;m, at each occurrence, is selected from 1, 2, 3, 4, and 5; n, at eachoccurrence, is selected from 0, 1, 2, 3, 4, and 5; o, at eachoccurrence, is selected from 1 and 2; p, at each occurrence, is selectedfrom 1 and 2; r, at each occurrence, is selected from.0, 1, 2, 3, 4, and5; q, at each occurrence, is selected from 1, 2, 3, 4, and 5; s, at eachoccurrence, is selected from 0, 1, and 2; t, at each occurrence, isselected from 0, 1, 2, 3, 4, and 5; u, at each occurrence, isindependently selected from 0, 1, and 2; v, at each occurrence, isselected from 0 and 1; and w, at each occurrence, is selected from 0, 1,2, and
 3. 2. The compound of claim 1, wherein: R⁴′ is absent or, takenwith the nitrogen to which it is attached to form an N-oxide; R⁷, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CHR′)_(q)OH,(CHR′)_(q)OR^(7d), (CHR′)_(q)NR^(7a)R^(7a)′, (CHR′)_(q)C(O)R^(7b),(CHR′)_(q)C(O)NR^(7a)R^(7a)′, (CHR′)_(q)NR^(7a)C(O)R^(7b),(CHR′)_(q)NR^(7a)C(O)H, (CHR′)_(q)S(O)₂NR^(7a)R^(7a)′,(CHR′)_(q)NR^(7a)S(O)₂R^(7b), (CHR′)_(q)NHC(O)NHR^(7a),(CHR′)_(q)NHC(O)OR^(7a), (CHR′)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a(CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c), and a(CHR′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7c); alternatively,R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, or ═NR^(8b); R¹¹, is selectedfrom H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl (CH₂)_(q)OH,(CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)C(O)R^(11b),(CH₂)_(q)NR^(11a)C(O)NHR^(11a), (CH₂)_(q)NHC(O)NH^(11a),(CH₂)_(q)NHC(O)OR^(11a), (CH₂)_(q)OC(O)NHR^(11a), C₁₋₆ haloalkyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(11c), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11c).
 3. The compoundof claim 2, wherein: A is selected from

t is selected from 0, 1, and
 2. 4. The compound of claim 3, wherein: R¹⁷is selected from H; and R¹⁸ is selected from H.
 5. The compound of claim4, wherein: A is selected from


6. The compound of claim 5, wherein: G is selected from —C(O)R³,—C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, and —SO₂R³, —C(═S)NR²R³,C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, C(═C(CN)₂)NR²R³, and


7. The compound of claim 6, wherein: G is selected from —C(O)NR²R³,²³C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³;8. The compound of claim 7, wherein: R¹⁶, at each occurrence, isselected from methyl, ethyl, propyl, iso-propyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 9. The compound of claim 8, wherein:R³ is selected from a (CR³′R³″)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R¹⁵ and a (CR³′CR³″)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, subsituted with0-2 R¹⁵; R³′ and R³″, at each occurrence, are selected from H; R¹⁵, ateach occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15f)R^(15f), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d),(CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, I, CN, (CF₂)_(r)CF₃, and OH.
 10. The compound of claim5, wherein: G is selected from


11. The compound of claim 10, wherein: R¹ is selected from H; both X¹and X² cannot be C; and Z² is selected from NR¹′, O and S.
 12. Thecompound of claim 11, wherein: R¹⁶, at each occurrence, is selected frommethyl, ethyl, propyl, iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a′), ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 13. The compound of claim 12,wherein: R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)(_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15f)R^(15f), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d),(CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); R′, at eachoccurrence, is selected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-⁶membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, I, CN, (CF₂)_(r)CF₃, and OH.
 14. The compound of claim2, wherein: A is selected from R R

v is selected from 0 and
 1. 15. The compound of claim 14, wherein: G isselected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, and —SO₂R³,—C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,C(═C(CN)₂)NR²R³, and


16. The compound of claim 15, wherein: G is selected from —C(O)NR²R³,²³C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³.17. The compound of claim 16, wherein: R¹⁶, at each occurrence, isselected from methyl, ethyl, propyl, iso-propyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 18. The compound of claim 17,wherein: R³ is selected from a (CR³′R³′)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R¹⁵ and a (CR³′CR³″)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, subsitutedwith 0-2 R¹⁵ R³′ and R³″, at each occurrence, are selected from H; R¹⁵,at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-⁶membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, I, CN, (CF₂)_(r)CF₃, and OH.
 19. The compound of claim14, wherein: G is selected from


20. The compound of claim 19, wherein: R¹ is H; both X¹ and X² cannot beC; and Z² is selected from NR¹′, O, and S.
 21. The compound of claim 20,wherein: R¹⁶, at each occurrence, is selected from methyl, ethyl,propyl, iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a)′,(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 22. The compound of claim 21,wherein: R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)OH, (CHR′)_(r)O (CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, I, CN, (CF₂)_(r)CF₃, and OH.
 23. The compound of claim1 wherein the compound is selected from:N-(3-acetylphenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride;N-(3-acetylphenyl)-N′-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureahydrochloride;N-(3-cyanophenyl)-N′-[(2R)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureatrifluoroacetate;N-(3-cyanophenyl)-N′-[(2R)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]ureatrifluoroacetate;N-(3-cyanophenyl)-N′-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;N-(3-cyanophenyl)-N′-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;N-(3-acetylphenyl)-N′-[(2S)-2-[[trans-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;N-(3-acetylphenyl)-N′-[(2S)-2-[[cis-4-[(4-fluorophenyl)methyl]-1-cyclohexyl]amino]-(1S)-1-cyclohexyl]ureatrifluoroacetate;N-(3-acetylphenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(3-acetylphenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(3-acetylphenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(3-acetylphenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(4-fluorophenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(4-fluorophenyl)-N′-[(2R)-2-[[(3R)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(4-fluorophenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1R)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(4-fluorophenyl)-N′-[(2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]-(1S)-1-cyclohexyl]amino]-(1R)-1-cyclohexyl]urea;N-(3-acetylphenyl)-N′-((3S,4S)-4-{[4-(4-fluorobenzyl)cyclohexyl]amino}tetrahydro-3-furanyl)urea;N-(3-acetylphenyl)-N′-({(2S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;N-(3-acetylphenyl])-N′-({(2S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;N-(3-acetylphenyl)-N′-({(2R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;N-(3-acetylphenyl)-N′-({(2R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methyl)urea;N-(3-acetylphenyl)-N′-{(3R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl]urea;N-(3-acetylphenyl)-N′-{(3R)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;N-(3-acetylphenyl)-N′-{(3S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea;andN-(3-acetylphenyl)-N′-{(3S)-1-[4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}urea.24. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 1. 25. A method for modulation of chemokine receptor activitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 26. A method for treating orpreventing inflammatory diseases, comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim
 1. 27. A method for treating or preventing asthma, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1.